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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Kolb H, Fernandez E, Jones B, et al., editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/webvision/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-webvision-lrg.png" alt="Cover of Webvision" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Webvision: The Organization of the Retina and Visual System [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK11552_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK11552_dtls__"><div>Kolb H, Fernandez E, Jones B, et al., editors.</div><div>Salt Lake City (UT): <a href="http://webvision.med.utah.edu/" ref="pagearea=page-banner&amp;targetsite=external&amp;targetcat=link&amp;targettype=publisher">University of Utah Health Sciences Center</a>; 1995-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/webvision/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/webvision/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/webvision/retinal_degeneration/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/webvision/ch38macular/" title="Next page in this title">Next &gt;</a></div></div></div></div></div>
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK11552_"><span class="title" itemprop="name">Cellular Remodeling in Mammalian Retina Induced by Retinal Detachment</span></h1><p class="contrib-group"><span itemprop="author">Steven K. Fisher</span>, <span itemprop="author">Geoffrey P. Lewis</span>, <span itemprop="author">Kenneth A. Linberg</span>, <span itemprop="author">Edward Barawid</span>, and <span itemprop="author">Mark R. Verardo</span>.</p><p class="small">Created: <span itemprop="datePublished">May 1, 2005</span>; Last Update: <span itemprop="dateModified">July 3, 2007</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="ch37fisher.Introduction"><h2 id="_ch37fisher_Introduction_">Introduction</h2><div id="ch37fisher.What_Is_Retinal_Deta"><h3>What Is Retinal Detachment?</h3><p>The retina is firmly attached to the apical surface of the retinal pigmented
epithelium, or RPE (see earlier retinal anatomy sections). When the retina is
separated from its normal position apposed to the RPE surface, it is said to be
"detached." This detachment creates a pathological, fluid-filled space between
the neural retina and the retinal pigmented epithelium. It also creates a
greater distance between the photoreceptors and their sole blood supply, the
choroidal circulation.</p></div><div id="ch37fisher.Clinical_Retinal_Det"><h3>Clinical Retinal Detachments Occur as Different Types</h3><p>There are three recognized types of retinal detachment in clinical practice:</p><dl class="temp-labeled-list"><dt>1.</dt><dd id="A4400"><p class="no_top_margin">Rhegmatogenous: the most common type. In this form, the retina
experiences a physical tear through the retinal layers, and the torn
retina peals away from the retinal pigmented epithelium by the movement
of fluid into the space between the two.</p></dd><dt>2.</dt><dd id="A4401"><p class="no_top_margin">Tractional: in which some force (usually contracting cells or vitreal
"strands") acts on the surface of the retina to pull it away from the
retinal pigmented epithelium.</p></dd><dt>3.</dt><dd id="A4402"><p class="no_top_margin">Exudative: in which fluid accumulates between the neural retina and the
retinal pigmented epithelium, pushing the two apart; the retinal tissue
is not torn.</p></dd></dl><p>Retinal detachment can cause permanent visual loss or permanent reduction of
visual function, especially if the macula is involved, in which case it is
considered a medical emergency in the United States. For more information on the
types and causes of retinal detachment, see the <a href="http://www.nei.nih.gov/health/retinaldetach/index.asp#I2" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">National Eye Institute's website</a>.</p></div><div id="ch37fisher._Cellular_Remodeling__1"><h3>Cellular Remodeling in the Retina</h3><p>Many specific neural circuits have been identified in the retina (<a class="bk_pop" href="#ch37fisher.EXTYLES.1">1-4</a>), and only
recently has evidence been found that these circuits change (remodel) in an
adult mammal, usually in response to injury and disease. Before this, the retina
was considered a "hard-wired" part of the central nervous system by most
scientists. A change in circuitry may mean a change in vision, so understanding
these changes and ways to prevent them or repair them is important.</p></div><div id="ch37fisher.Some_Examples_of_Ret"><h3>Some Examples of Retinal Remodeling</h3><p>The few earlier descriptions of cellular remodeling in vertebrate retina came
from studies of fish retinas (<a class="bk_pop" href="#ch37fisher.EXTYLES.5">5-7</a>),
where specific synaptic connections between photoreceptors and second-order
neurons structurally changed with the daily lighting cycle. In 1984, Peichl and
Bolz (<a class="bk_pop" href="#ch37fisher.EXTYLES.8">8</a>) described
structural remodeling of retinal neurons in mammals in response to severe
retinal degeneration induced by a neurotoxin, kainic acid. It was nearly a
decade later that reports of cellular remodeling in mammalian retina in response
to injury or disease began to appear with some regularity (<a class="bk_pop" href="#ch37fisher.EXTYLES.9">9-12</a>).
Even total photoreceptor cell loss had not been regarded as causing significant
changes to the inner retina until that time.</p></div><div id="ch37fisher.Photoreceptor_Cell_D"><h3>Photoreceptor Cell Death Differs Among Models</h3><p>Many recent descriptions of structural remodeling in mammalian retina are from
studies in humans or rodent species in which massive photoreceptor cell death is
induced by light damage or genetic mutations (<a class="bk_pop" href="#ch37fisher.EXTYLES.13">13</a>). Retinal detachment provides
information that complements those data because in most species there is not
massive photoreceptor cell death after detachment. Another important distinction
is that the earliest and most obvious damage induced by detachment, outer
segment degeneration, is reversible by reattaching the retina. Retinal
reattachment surgery probably induces its own remodeling of retinal circuits as
recovery occurs, but this has been less explored at the present time.</p></div><div id="ch37fisher.Retinal_Detachment_a"><h3>Retinal Detachment and Reattachment as Experimental Systems</h3><p><a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" rid-figpopup="figch37fisherF1" rid-ob="figobch37fisherF1">Fig.
1</a> illustrates cell types observed to remodel after detachment, these
include: RPE, Muller cells, photoreceptors, rod bipolar cells, horizontal cells,
ganglion cells, and astrocytes. It seems likely that remodeling will be
identified in other cell types as well.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF1" co-legend-rid="figlgndch37fisherF1"><a href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF1" rid-ob="figobch37fisherF1"><img class="small-thumb" src="/books/NBK11552/bin/fisherf1.gif" src-large="/books/NBK11552/bin/fisherf1.jpg" alt="Figure 1. A drawing of the relevant retinal cell types discussed in this review." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF1"><h4 id="ch37fisher.F1"><a href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" rid-ob="figobch37fisherF1">Figure 1</a></h4><p class="float-caption no_bottom_margin">A drawing of the relevant retinal cell types discussed in this
review. Blood vessels of the choriocapillaris lie adjacent to the retinal
pigmented epithelium (RPE), opposite the retina. A, astrocytes; atB, axon
terminal of B-type horizontal cell (HB); <a href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" rid-ob="figobch37fisherF1">(more...)</a></p></div></div><p>Outer segment degeneration, photoreceptor cell death, Muller cell hypertrophy,
and changes in the RPE apical surface were all recognized as events induced by
detachment in early studies (<a class="bk_pop" href="#ch37fisher.EXTYLES.14">14-16</a>).
More recently, studies have demonstrated photoreceptor cell death occurs by
apoptosis in both animals and humans. Currently, there is no method for
replacing lost photoreceptors. Other events may be reversed by reattachment,
often incompletely and usually slowly, over a time course that can vary from
days to years.</p></div><div id="ch37fisher.Why_Remodeling_Is_Di"><h3>Why Remodeling Is Difficult to Discover</h3><p>The huge numbers of neurons and glial cells involved in the retina, the vast
range of neuronal cell architectures, the small size of neuronal cell bodies
relative to other cells, and the small size of the neuronal processes that
intertwine to make up the plexiform layers of the retina make discovery of
subtle changes in these cells difficult. Historically, it was the Golgi
impregnation method that provided the breakthrough allowing for a detailed
description of individual neurons and their morphologic diversity (<a class="bk_pop" href="#ch37fisher.EXTYLES.17">17</a>). A similar reliable
method that would allow us to observe changes in the branching of individual
neurons would be ideal for studying remodeling. Unfortunately, the Golgi method
is unreliable and quixotic and, therefore, does not provide a method for the
systematic study of events such a neuronal remodeling. What will undoubtedly
emerge as technology evolves will be the invaluable tools for observing
structural remodeling of retinal neurons in living tissue.</p></div><div id="ch37fisher.Making_Use_of_New_Te"><h3>Making Use of New Technology to Describe Remodeling Events</h3><p>Immunocytochemistry and other techniques that allow for the labeling of
individual cells or populations of cells, coupled with advances in image
technology such as laser scanning and confocal microscopy, have provided us with
new and powerful tools for describing remodeling events in the retina in recent
years.</p><p>Rod photoreceptor, rod bipolar, and horizontal cell remodeling (<a class="bk_pop" href="#ch37fisher.EXTYLES.11">11</a>) was the
first to be studied in detail with this technology. In fact, results with
antibody labeling confirmed speculation based on electron microscopy data
published in 1983: "In addition to the effects of retinal detachment in the
outer retina, we strongly suspect that the inner nuclear layer, IPL, ganglion
cell layer and, perhaps, more central areas of the visual system may be affected
as well" (<a class="bk_pop" href="#ch37fisher.EXTYLES.15">15</a>).
Remodeling has now been firmly established in the inner retina and leads one to
believe more strongly that central changes, for example ganglion cell axonal
arborization and synaptic contacts, will be eventually identified as well.
Technologies involving other forms of imaging, including the imaging of living
cells in retinal wholemounts or tissue slices and techniques such as dye
injection into single cells, will undoubtedly contribute greatly to this rapidly
growing knowledge base.</p></div></div><div id="ch37fisher.Levels_of_Remodeling"><h2 id="_ch37fisher_Levels_of_Remodeling_">Levels of Remodeling</h2><p>Remodeling can involve whole populations of cells; for instance, all RPE cells
remodel their apical processes (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2">Fig. 2</a>, A-C, asterisk), and all
photoreceptors undergo outer segment degeneration after detachment, or it can
involve some subset of cells within a population. The apical surface of every RPE
cell must remodel in response to both detachment and reattachment as the complex
apical processes are transformed into microvilli after detachment and then
regenerated after reattachment. Interestingly, the remodeling after reattachment
does not appear to be consistent from cell to cell (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2">Fig. 2</a>, D and E). Thus, regeneration of the apical
surface is not a perfect recapitulation of development. All Muller cells in the zone
of detachment upregulate intermediate filament proteins, and all probably undergo
some structural remodeling, but only some show extreme changes where they actually
grow out of the retina, creeping into the subretinal space or onto the vitreal
surface. Both of these conditions result in serious, sight-threatening, ophthalmic
complications. Defining what stimulates this subpopulation to undergo such growth is
medically important. Only a subpopulation of ganglion cells appears to remodel in
response to detachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>), and
identifying which types may lead to a better understanding of some of the visual
disturbances that occur after successful reattachment surgery.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF2" co-legend-rid="figlgndch37fisherF2"><a href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2"><img class="small-thumb" src="/books/NBK11552/bin/fisherf2.gif" src-large="/books/NBK11552/bin/fisherf2.jpg" alt="Figure 2. Electron microscopy." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF2"><h4 id="ch37fisher.F2"><a href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-ob="figobch37fisherF2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Electron microscopy. A, normal feline retina. Rod outer segments
(ROS, R) terminate close to the retinal pigmented epithelium (RPE). Cone
outer segments (COS) are shorter and surrounded by an elaborate cone sheath
arising from specialized apical processes. <a href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-ob="figobch37fisherF2">(more...)</a></p></div></div><div id="ch37fisher.Retinal_Deafferentat"><h3>Retinal Deafferentation</h3><p>Deafferentation in the central nervous system (CNS) refers to removing the
sensory input from some motor pathway. Although there is no "motor" component to
the retina's output to the brain, the massive loss of photoreceptors (usually
approaching 100%) that occurs in some diseases such as retinitis pigmentosa (or
in animal models of this disease) has been described as "deafferentation" (<a class="bk_pop" href="#ch37fisher.EXTYLES.13">13</a>). Remodeling in these
systems and in such conditions as light damage in albino rats has been described
as largely in response to this "deafferentation". The changes that we are
focused on here are those that occur within hours or days of detachment, because
it is these changes that may be successfully manipulated by therapeutic
intervention and thus lead to better visual recovery. These are not responses to
massive death of photoreceptors, although they may represent responses to the
death of individual photoreceptors and therefore partial deafferentation of
individual cells or neural circuits. Remodeling is also associated with the
recovery phase after retinal reattachment, during a time when photoreceptor cell
death does not occur.</p></div><div id="ch37fisher.Basic_Information_Re"><h3>Basic Information Relevant to Understanding the Responses to Retinal
Detachment</h3><p>Although the retina is a developmental outgrowth of the brain, it does have
several features unique to its specialized functions. Photoreceptors have the
highest metabolic rate of any cells in the body, and yet there are no blood
vessels among them (their presence presumably would blur the visual
image)&#x02014;they are nourished almost solely by the capillaries of the
choroid, which lie on the opposite side of the RPE (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" rid-figpopup="figch37fisherF1" rid-ob="figobch37fisherF1">Fig. 1</a>) (<a class="bk_pop" href="#ch37fisher.EXTYLES.19">19</a>).
Traditional astrocytes are not scattered throughout the retina as they are in
the brain and spinal cord but reside only among the ganglion cells and their
axons. The retina has a large population of highly differentiated, polarized
radial glia, or Muller cells, that may assume many of the functions of
astrocytes in the brain and spinal cord but are, at the same time, distinct from
them. Ganglion cell axons in most species are not myelinated until after they
enter the optic nerve, and thus, the retina does not have a population of
oligodendrocytes, the myelin-producing glial cells. The retina does have a
resident population of microglial (scavenger) cells, but these appear to be
restricted to the IPLs and outer plexiform layers (OPLs) in the healthy eye.</p></div><div id="ch37fisher.Animal_Models_of_Det"><h3>Animal Models of Detachment and Reattachment</h3><p>The choice of which species to use has been driven by many issues including: 1)
how closely the retina structurally resembles that of humans; 2) knowledge of
retinal circuitry, physiology, or biochemistry in the species; 3) the
reliability with which controlled detachments and reattachments can be created;
and 4) the specific goals of the study.</p></div><div id="ch37fisher.Different_Species_Re"><h3>Different Species React Differently: Finding the Best Model</h3><p>Different species do react differently to detachment, and not all of these
accurately reflect what little we know about the reaction of the human retina.
The rabbit retina (with about the same rod/cone ratio as the feline retina)
exhibits very rapid and complete degeneration of much of the neural retina
(<a class="bk_pop" href="#ch37fisher.EXTYLES.20">20</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.21">21</a>); thus, it is not a
good model for longer-term events. The ground squirrel has a retina dominated by
cones (<a class="bk_pop" href="#ch37fisher.EXTYLES.22">22</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.23">23</a>)
and thus is a potential model for the reactivity of the human macula (except
that ground squirrel cones do not structurally resemble macular cones). The
ground squirrel retina, however, shows a rapid and eventually complete
degeneration of the photoreceptor layer but almost no RPE or glial reactivity or
neuronal remodeling (<a class="bk_pop" href="#ch37fisher.EXTYLES.24">24</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.25">25</a>).
Unlike the rabbit, it does not show inner retinal degeneration. We have used all
of these in various studies, but the species that seems to most closely model
what is known about events in human detachments is the common domestic cat. The
retina of many primate species are foveated, but their use is often prohibitive
for a variety of ethical and financial reasons.</p></div><div id="ch37fisher.Developing_New_Model"><h3>Developing New Model Systems</h3><p>Because of the availability of genetic information and the ability to readily do
genetic manipulations, developing a reliable method for producing large,
controlled detachments in the mouse eye has become a high priority in recent
years (e.g., Nour et al. (<a class="bk_pop" href="#ch37fisher.EXTYLES.26">26</a>) and
Yang et al. (<a class="bk_pop" href="#ch37fisher.EXTYLES.27">27</a>)). Current
data from that model show many of the same reactions found in the feline model,
although there may be less Muller cell reactivity. The height of a detachment,
that is, the distance separating the detached neural retina from the RPE, is
probably an important parameter in human detachments, and high detachments are
harder to produce in mice because of the small size of the eye and the fact that
the lens fills much of the vitreous cavity. Reattachments using the same
procedures as in humans can be done in larger species; whether they will be
possible in a mouse eye remains to be seen. Simply allowing the retina to settle
instead of actively reattaching it provides one method, but with less precise
control over the time of reattachment. Another promising area is the use of
cold-blooded animals (e.g., frogs, fish, and salamanders) in similar experiments
because their retinas are relatively easy to maintain in culture, and because
many of them have very large photoreceptor cells that are amenable for
high-resolution imaging and other types of single-cell analyses. Currently, most
work is, however, being done with mammalian species.</p></div><div id="ch37fisher.The_Feline_Model"><h3>The Feline Model</h3><p>The feline retina, similar to the peripheral human retina, is rod dominated. It
is a species with a robust intraretinal circulation (as in all species, it is
excluded from the photoreceptors). The cat retina has also been the subject of
decades worth of anatomical and physiological studies. The feline eye is large,
allowing for easy surgical access, and for the production of defined detachments
and simple reattachments using the same procedures as in human patients.</p><p>Detachments are created by slowly infusing fluid into the interface between the
RPE and neural retina through a tapered glass pipette with a tip diameter of
about 100 &#x003bc;m (<a class="bk_pop" href="#ch37fisher.EXTYLES.28">28</a>). It
has been argued (<a class="bk_pop" href="#ch37fisher.EXTYLES.29">29</a>)
that this does not model a rhegmatogenous detachment because there is no large
tear (referred to as a "retinal break") through the retinal tissue. However, our
observations of tissue from human rhegmatogenous detachments and reattachments
tend to validate the feline model as producing the same cellular responses
(<a class="bk_pop" href="#ch37fisher.EXTYLES.30">30</a>).</p></div></div><div id="ch37fisher.The_Details_of_Cellu"><h2 id="_ch37fisher_The_Details_of_Cellu_">The Details of Cellular Remodeling after Detachment and Reattachment</h2><p><a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F1/?report=objectonly" target="object" rid-figpopup="figch37fisherF1" rid-ob="figobch37fisherF1">Fig. 1</a> shows the cell types that have
been identified to date as undergoing remodeling after detachment and reattachment.
We have only preliminary evidence for the structural remodeling of amacrine cells,
although this has been described in late-stage human retinitis pigmentosa (<a class="bk_pop" href="#ch37fisher.EXTYLES.10">10</a>). Little is
known about changes in retinal astrocytes except that they proliferate after
detachment. Retinal microglia respond robustly to detachment by assuming
macrophage-like characteristics (<a class="bk_pop" href="#ch37fisher.EXTYLES.31">31</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.32">32</a>). They
will not be discussed here, although they undoubtedly play an important role in the
overall "injury response" of the retinal tissue.</p><div id="ch37fisher.Retinal_Pigmented_Ep"><h3>Retinal Pigmented Epithelium</h3><p>The morphology of the RPE changes stereotypically after detachment in all species
studied. In species such as cat, dog, rabbit, and human, there are vast
differences between the apical processes that interact with rods and cones
(<a class="bk_pop" href="#ch37fisher.EXTYLES.33">33-36</a>),
with the "cone sheath" forming a unique structure consisting of a highly
complex, multi-layered array of sheets of apical processes (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2">Fig. 2</a>, A, and B). Regardless of their structure
in the normal eye, these apical processes all disappear after detachment and are
replaced very quickly, probably within hours, by a fringe of simple
microvillus-like processes (<a class="bk_pop" href="#ch37fisher.EXTYLES.37">37</a>) (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2">Fig. 2</a>, C, asterisk). The RPE has
the remarkable ability to re-form these elaborate apical processes after
reattachment. In the case of the feline retina, this also means regenerating the
highly complex cone sheaths. However, a month after reattachment, these cone
sheaths still do not appear "normal". The presence of slightly truncated, often
thickened or misaligned, cone sheaths is almost always a clear indicator that
the retina was detached at some earlier time (compare the structures labeled
"CS" in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F2/?report=objectonly" target="object" rid-figpopup="figch37fisherF2" rid-ob="figobch37fisherF2">Fig. 2</a>, A, B, D, and E).
The fact that the cone sheaths re-differentiate only in association with cone
outer segments indicates some form of signaling mechanism retained in the adult
retina that allows for the RPE to know when its apical surface is opposite a
cone.</p><p>The RPE proliferates in response to detachment, and this can result in a complete
remodeling of the geometry of this layer. Newly proliferated RPE cells can
migrate into the subretinal space, where they assume complex geometric
arrangements: single cells, long strands, or multiple layers with reversed
apical-basal polarity (<a class="bk_pop" href="#ch37fisher.EXTYLES.38">38</a>). If
the basal surface faces the neural retina, photoreceptor outer segment
regeneration does not occur after reattachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.39">39</a>). It is not
known if photoreceptor function is compromised when outer segments regenerate in
the presence of multiple layers of RPE.</p></div><div id="ch37fisher.Photoreceptor_Decons"><h3>Photoreceptor Deconstruction, Outer Segment Degeneration, and Cell
Death</h3><p>In the feline model, and probably in the human retina, detachment sends all of
the photoreceptors, both rods and cones, within the zone of detachment, along a
pathway of structural changes that we have termed "deconstruction" (<a class="bk_pop" href="#ch37fisher.EXTYLES.40">40</a>). The outer
and inner segment response appears to be the same in rods and cones, but the
synaptic terminal responses differ. In both feline and human retinas, it is
clear that many cells survive detachment for very long periods of time.
Deconstructive changes may occur as a mechanism to assure the cells' survival
under adverse environmental conditions, i.e., a means of saving metabolic
energy. It is not clear why in some species (ground squirrel, rabbit) detachment
leads to deconstruction and cell death of virtually all photoreceptors, whereas
in other species, the majority survive for long periods of time.</p><p>After detachment, outer segment material is lost until only a few disks remain,
along with the connecting cilium (<a class="bk_pop" href="#ch37fisher.EXTYLES.14">14</a>). The
complex mechanism of disc morphogenesis is not lost in these cells (<a class="bk_pop" href="#ch37fisher.EXTYLES.41">41</a>) because
once reattached, they retain their ability to reconstruct an outer segment even
though that reconstruction may not be perfect. Remaining rod photoreceptor outer
segments, even if composed of only a few discs (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-figpopup="figch37fisherF3" rid-ob="figobch37fisherF3">Fig. 3</a>, A-C)
are still positive for their respective opsins (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-figpopup="figch37fisherF3" rid-ob="figobch37fisherF3">Fig. 3</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F4/?report=objectonly" target="object" rid-figpopup="figch37fisherF4" rid-ob="figobch37fisherF4">Fig. 4</a>) (<a class="bk_pop" href="#ch37fisher.EXTYLES.42">42</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.43">43</a>)
as well as other proteins.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF3" co-legend-rid="figlgndch37fisherF3"><a href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF3" rid-ob="figobch37fisherF3"><img class="small-thumb" src="/books/NBK11552/bin/fisherf3.gif" src-large="/books/NBK11552/bin/fisherf3.jpg" alt="Figure 3. Normal and detached retina labeled with an antibody to rod opsin." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF3"><h4 id="ch37fisher.F3"><a href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-ob="figobch37fisherF3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Normal and detached retina labeled with an antibody to rod opsin.
A, normal retina. Rod outer segments (OS) are labeled. B, retina detached
for 3 days. The OS layer narrows as rod OS degenerate, and the antibody now
labels the plasma membrane of rod cells <a href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-ob="figobch37fisherF3">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF4" co-legend-rid="figlgndch37fisherF4"><a href="/books/NBK11552/figure/ch37fisher.F4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF4" rid-ob="figobch37fisherF4"><img class="small-thumb" src="/books/NBK11552/bin/fisherf4.gif" src-large="/books/NBK11552/bin/fisherf4.jpg" alt="Figure 4. Normal and detached retina labeled with an antibody to medium (M)- and long (L)-wavelength-sensitive cone opsins." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF4"><h4 id="ch37fisher.F4"><a href="/books/NBK11552/figure/ch37fisher.F4/?report=objectonly" target="object" rid-ob="figobch37fisherF4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Normal and detached retina labeled with an antibody to medium (M)-
and long (L)-wavelength-sensitive cone opsins. A, in normal retina all M-COS
are labeled. B, retina detached for 3 days. The M-COS are degenerating, and
the antibody labels the plasma <a href="/books/NBK11552/figure/ch37fisher.F4/?report=objectonly" target="object" rid-ob="figobch37fisherF4">(more...)</a></p></div></div></div><div id="ch37fisher.Death_by_Apoptosis"><h3>Death by Apoptosis</h3><p>Most photoreceptor cell death after detachment is by apoptosis (programmed cell
death). On the basis of our results in the feline retina, there is an early
period, around the first 3 days after detachment, when about 20% of the
photoreceptors die by apoptosis (<a class="bk_pop" href="#ch37fisher.EXTYLES.44">44</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.45">45</a>),
but retinas detached for 450 days can retain at least 50% of their
photoreceptors (<a class="bk_pop" href="#ch37fisher.EXTYLES.15">15</a>).
Observations of human detachments also show that apoptosis is a part of their
response to detachment, but as in the feline model, large portions of the
photoreceptor population also survive (<a class="bk_pop" href="#ch37fisher.EXTYLES.46">46</a>). There is no information about the
survivability of foveal photoreceptors after detachment. Cell death in the inner
retina in response to detachment is very rarely observed in the feline model;
although sporadic cell death may be important, it is also difficult to
document.</p></div><div id="ch37fisher.Internal_Reorganizat"><h3>Internal Reorganization of Photoreceptor Inner Segments</h3><p>After detachment, electron microscopy as well as immunocytochemical labeling for
mitochondrial components shows a decrease in the number of mitochondria in the
inner segments as well as a much less distinctive compartmentalization of all
organelles (<a class="bk_pop" href="#ch37fisher.EXTYLES.14">14</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.15">15</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.40">40</a>).
Maintaining the highly compartmentalized and polarized structure of a
photoreceptor must be metabolically costly. Having the cells assume a much
simpler organization may assure their survival under environmentally challenging
conditions. In the case of detachment, that challenge would include hypoxia and
probably hypoglycemia that is created by physically moving the retina away from
its choroidal blood supply (<a class="bk_pop" href="#ch37fisher.EXTYLES.19">19</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.28">28</a>,
<a class="bk_pop" href="#ch37fisher.EXTYLES.40">40</a>).
This hypothesis is supported by studies in which providing increased
environmental oxygen lessens photoreceptor deconstruction and cell death after
detachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.25">25</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.28">28</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.47">47</a>).</p></div><div id="ch37fisher.A_Comparison_of_Rod_"><h3>A Comparison of Rod and Cone Responses</h3><p>The outer and inner segment of rods and cones undergo similar structural changes,
but a prominent response of rods is the withdrawal of their axons (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5">Fig.
5</a>, A and B) and a reconfiguration of the single synaptic invagination
with its 3-5 postsynaptic processes (<a class="bk_pop" href="#ch37fisher.EXTYLES.48">48</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.49">49</a>).
This response is not observed in cones.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF5" co-legend-rid="figlgndch37fisherF5"><a href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5"><img class="small-thumb" src="/books/NBK11552/bin/fisherf5.gif" src-large="/books/NBK11552/bin/fisherf5.jpg" alt="Figure 5. A, normal retina labeled with an antibody to the presynaptic protein, synaptophysin." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF5"><h4 id="ch37fisher.F5"><a href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-ob="figobch37fisherF5">Figure 5</a></h4><p class="float-caption no_bottom_margin">A, normal retina labeled with an antibody to the presynaptic
protein, synaptophysin. Labeling is specific to the layer of photoreceptor
synaptic terminals in the OPL. B, retina detached for 3 days. The compact
OPL is disrupted, and RS retract into the <a href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-ob="figobch37fisherF5">(more...)</a></p></div></div><p>This disruption can be appreciated by immunocytochemical labeling with antibodies
to presynaptic vesicle proteins, such as synaptophysin (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5">Fig. 5</a>) or VAMP (synaptobrevin). After
detachment, labeled terminals appear near the rod nuclei scattered throughout
the outer nuclear layer (ONL) (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5">Fig.
5</a>B). Terminal withdrawal and reorganization begins within a day. The
electron micrograph in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F6/?report=objectonly" target="object" rid-figpopup="figch37fisherF6" rid-ob="figobch37fisherF6">Fig. 6</a> shows the highly compact
organization of the rod terminals in the OPL in a normal feline retina. After
detachment, the deep synaptic invagination in each becomes more shallow (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig.
7</a>, A and B, arrows) and is eventually lost altogether (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig. 7</a>, C and D). There are still
membrane specializations associated with the "postsynaptic" processes adjacent
to the base of the retracted terminals (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig. 7</a>, B-D). Those terminals that do not retract may also change
with a "looser" organization of postsynaptic processes (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig. 7</a>B).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF6" co-legend-rid="figlgndch37fisherF6"><a href="/books/NBK11552/figure/ch37fisher.F6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF6" rid-ob="figobch37fisherF6"><img class="small-thumb" src="/books/NBK11552/bin/fisherf6.gif" src-large="/books/NBK11552/bin/fisherf6.jpg" alt="Figure 6. The OPL of normal feline retina." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF6"><h4 id="ch37fisher.F6"><a href="/books/NBK11552/figure/ch37fisher.F6/?report=objectonly" target="object" rid-ob="figobch37fisherF6">Figure 6</a></h4><p class="float-caption no_bottom_margin">The OPL of normal feline retina. RS lie just distal to the OPL. R,
rod nuclei in the ONL. Scale bar, 2 &#x003bc;m. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF7" co-legend-rid="figlgndch37fisherF7"><a href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7"><img class="small-thumb" src="/books/NBK11552/bin/fisherf7.gif" src-large="/books/NBK11552/bin/fisherf7.jpg" alt="Figure 7. A, normal retina." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF7"><h4 id="ch37fisher.F7"><a href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-ob="figobch37fisherF7">Figure 7</a></h4><p class="float-caption no_bottom_margin">A, normal retina. Organized postsynaptic processes enter the
synaptic invagination (arrow) of the RS. Arrowhead, presynaptic ribbon in a
RS. B, in a detached retina, the synaptic invaginations (arrows) are
flatter, and post-synaptic processes are less <a href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-ob="figobch37fisherF7">(more...)</a></p></div></div><p>Withdrawn rod terminals show a sparse population of synaptic vesicles and
synaptic ribbons that vary more in size, configuration, and location than
expected. Although there are one or two long, arc-shaped synaptic ribbons in
normal feline rod spherules (<a class="bk_pop" href="#ch37fisher.EXTYLES.48">48</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.50">50</a>),
the presence of 1-3 shortened ribbons is common in the retracted terminals
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig. 7</a>, A, C, and D,
arrowheads).</p><p>Cone pedicles do not withdraw from the OPL. However, the pedicle itself undergoes
unpredictable changes in shape. The axons of some become tortuous instead of
streaming straight across the ONL from their cell body (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" rid-figpopup="figch37fisherF8" rid-ob="figobch37fisherF8">Fig. 8</a>, A-C).
In all cases, however, these terminals appear to lose the 9-14 synaptic
invaginations (<a class="bk_pop" href="#ch37fisher.EXTYLES.48">48</a>) (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" rid-figpopup="figch37fisherF9" rid-ob="figobch37fisherF9">Fig.
9</a>, A and B), giving their base a flattened appearance (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" rid-figpopup="figch37fisherF8" rid-ob="figobch37fisherF8">Fig. 8</a>C) (also see Erickson et al.
(<a class="bk_pop" href="#ch37fisher.EXTYLES.15">15</a>)).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF8" co-legend-rid="figlgndch37fisherF8"><a href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" title="Figure 8" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF8" rid-ob="figobch37fisherF8"><img class="small-thumb" src="/books/NBK11552/bin/fisherf8.gif" src-large="/books/NBK11552/bin/fisherf8.jpg" alt="Figure 8. Expression of the g subunit of the photoreceptor-specific phosphodiesterase (PDAg)." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF8"><h4 id="ch37fisher.F8"><a href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" rid-ob="figobch37fisherF8">Figure 8</a></h4><p class="float-caption no_bottom_margin">Expression of the g subunit of the photoreceptor-specific
phosphodiesterase (PDAg). A, normal retina. The antibody labels both rod and
cone outer segments (OS), and cones in their entirety. B, CP labeling in
normal retina. Arrowheads, fine telodendria. <a href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" rid-ob="figobch37fisherF8">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF9" co-legend-rid="figlgndch37fisherF9"><a href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" title="Figure 9" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF9" rid-ob="figobch37fisherF9"><img class="small-thumb" src="/books/NBK11552/bin/fisherf9.gif" src-large="/books/NBK11552/bin/fisherf9.jpg" alt="Figure 9. Cone synapses." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF9"><h4 id="ch37fisher.F9"><a href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" rid-ob="figobch37fisherF9">Figure 9</a></h4><p class="float-caption no_bottom_margin">Cone synapses. Electron micrographs of CP (outlined white) in
normal (A) and detached (B) retina. Post-synaptic processes outlined with
blue. Notice lack of deep invaginations and reduced number of post-synaptic
processes after detachment. The population <a href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" rid-ob="figobch37fisherF9">(more...)</a></p></div></div></div><div id="ch37fisher.Presynaptic_Ribbons_"><h3>Presynaptic Ribbons Change in Both Rods and Cones</h3><p>Presynaptic ribbons appear to grow shorter, and some may disappear (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" rid-figpopup="figch37fisherF9" rid-ob="figobch37fisherF9">Fig. 9</a>, A and B). This ribbon
response is dramatic when observed by immunocytochemical labeling using
antibodies specific to them (<a class="bk_pop" href="#ch37fisher.EXTYLES.51">51</a>).
Ribbons in rod terminals appear as "clumps" (compare the red synaptic ribbons in
<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-figpopup="figch37fisherF10" rid-ob="figobch37fisherF10">Fig. 10</a>, B and C, to those in
<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-figpopup="figch37fisherF10" rid-ob="figobch37fisherF10">Fig. 10</a>, D). Within the
cone pedicles, the characteristic array of ribbons (Fig. 10, C, arrowheads) is
no longer detected in the OPL (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-figpopup="figch37fisherF10" rid-ob="figobch37fisherF10">Fig.
10</a>D). By electron microscopy, very short ribbons remain within the
affected cone terminals, and some post-synaptic processes are still recognizable
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F9/?report=objectonly" target="object" rid-figpopup="figch37fisherF9" rid-ob="figobch37fisherF9">Fig. 9</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF10" co-legend-rid="figlgndch37fisherF10"><a href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF10" rid-ob="figobch37fisherF10"><img class="small-thumb" src="/books/NBK11552/bin/fisherf10.gif" src-large="/books/NBK11552/bin/fisherf10.jpg" alt="Figure 10. Labeling with anti-PDEg (green; see Fig." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF10"><h4 id="ch37fisher.F10"><a href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-ob="figobch37fisherF10">Figure 10</a></h4><p class="float-caption no_bottom_margin">Labeling with anti-PDEg (green; see Fig. 8) and with anti-CtBP2
(red), which labels synaptic ribbons. A, normal retina. The antibody to
CtBP2 labels synaptic ribbons in rod and cone synaptic endings (green). B,
normal retina. CP contain many ribbons (their <a href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-ob="figobch37fisherF10">(more...)</a></p></div></div><p>Following the remodeling of rod terminals has been made relatively simple because
of their outlining by displaced rhodopsin. Documenting longer-term changes in
cone synapses is complicated by the fact that the expression of proteins in the
cones rapidly decreases to levels that are below detection (<a class="bk_pop" href="#ch37fisher.EXTYLES.52">52</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.53">53</a>),
making them difficult to visualize by immunocytochemistry. (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F8/?report=objectonly" target="object" rid-figpopup="figch37fisherF8" rid-ob="figobch37fisherF8">Fig. 8</a>, A-D). In <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F11/?report=objectonly" target="object" rid-figpopup="figch37fisherF11" rid-ob="figobch37fisherF11">Fig. 11</a>, there
are long expanses of the retina in which only the rod outer segments (green) are
labeled by the anti-PDEg, and there are no labeled cones.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF11" co-legend-rid="figlgndch37fisherF11"><a href="/books/NBK11552/figure/ch37fisher.F11/?report=objectonly" target="object" title="Figure 11" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF11" rid-ob="figobch37fisherF11"><img class="small-thumb" src="/books/NBK11552/bin/fisherf11.gif" src-large="/books/NBK11552/bin/fisherf11.jpg" alt="Figure 11. A 7-day detached retina." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF11"><h4 id="ch37fisher.F11"><a href="/books/NBK11552/figure/ch37fisher.F11/?report=objectonly" target="object" rid-ob="figobch37fisherF11">Figure 11</a></h4><p class="float-caption no_bottom_margin">A 7-day detached retina. Demonstrates the prominent reduction in
labeling with cone-specific antibodies after detachment. Labeled with the
anti-PDEg (green) and CtBP2 (red). Rod outer segments (OS) still label with
the antibody to PDEg, but there is a <a href="/books/NBK11552/figure/ch37fisher.F11/?report=objectonly" target="object" rid-ob="figobch37fisherF11">(more...)</a></p></div></div></div><div id="ch37fisher.The_Population_of_Co"><h3>The Population of Cones Is Heterogeneous</h3><p>The lectin, peanut agglutinin (PNA), labels the extracellular matrix domain
(matrix sheath) around cone photoreceptors (<a class="bk_pop" href="#ch37fisher.EXTYLES.54">54</a>) and can be
used to define the total population of cone cells. <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12">Fig. 12</a>A is a
density map of PNA-labeled cone sheaths in the superior temporal quadrant of a
control (normal) feline retina (also see Steinberg et al. (<a class="bk_pop" href="#ch37fisher.EXTYLES.55">55</a>)).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF12" co-legend-rid="figlgndch37fisherF12"><a href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" title="Figure 12" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12"><img class="small-thumb" src="/books/NBK11552/bin/fisherf12.gif" src-large="/books/NBK11552/bin/fisherf12.jpg" alt="Figure 12. The lectin peanut agglutinin (PNA) binds to extracellular matrix around the cone outer segments (COS; cone matrix sheath) as seen in wholemount retinas." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF12"><h4 id="ch37fisher.F12"><a href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-ob="figobch37fisherF12">Figure 12</a></h4><p class="float-caption no_bottom_margin">The lectin peanut agglutinin (PNA) binds to extracellular matrix
around the cone outer segments (COS; cone matrix sheath) as seen in
wholemount retinas. The wholemounts were photographed, and the number of
labeled cone sheaths were counted and expressed <a href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-ob="figobch37fisherF12">(more...)</a></p></div></div><p>There are specific antibodies that recognize the different spectral classes of
cone photoreceptors (<a class="bk_pop" href="#ch37fisher.EXTYLES.56">56-58</a>).
The feline retina contains mid-wavelength-sensitive (M) and
short-wavelength-sensitive (S) cones, and the latter are not distributed evenly
over the retinal topography (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-figpopup="figch37fisherF3" rid-ob="figobch37fisherF3">Fig.
3</a>A). Whereas the total number of cones peaks in the area centralis,
the density of S-cones is highest in the inferior retina, but even there, they
compose only about 20% of the cone population (<a class="bk_pop" href="#ch37fisher.EXTYLES.52">52</a>).</p><p>The expression of opsin genes reliably defines distinct subpopulations of
photoreceptors. The expression of other proteins by these cells is less
consistent. An antibody to the calcium binding protein calbindin D labels entire
cone cells in many species, including humans and felines. The density of
calbindin D-positive cells matches very closely the density of PNA-labeled cone
matrix sheathes in the peripheral retina, but there is significant disparity in
the area centralis, where the antibody fails to label a majority of cones (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-figpopup="figch37fisherF14" rid-ob="figobch37fisherF14">Fig. 14</a>A). This phenomenon also
occurs in monkey and human retinas, where foveal cones do not label with
anti-calbindin D (<a class="bk_pop" href="#ch37fisher.EXTYLES.59">59-61</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF14" co-legend-rid="figlgndch37fisherF14"><a href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" title="Figure 14" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF14" rid-ob="figobch37fisherF14"><img class="small-thumb" src="/books/NBK11552/bin/fisherf14.gif" src-large="/books/NBK11552/bin/fisherf14.jpg" alt="Figure 14. Isodensity contours for cones labeled with an antibody to the calcium binding protein calbindin D in normal (left) and detached (right) feline retinas." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF14"><h4 id="ch37fisher.F14"><a href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-ob="figobch37fisherF14">Figure 14</a></h4><p class="float-caption no_bottom_margin">Isodensity contours for cones labeled with an antibody to the
calcium binding protein calbindin D in normal (left) and detached (right)
feline retinas. In the periphery, this antibody binds to all cone outer
segments except in the area centralis, where <a href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-ob="figobch37fisherF14">(more...)</a></p></div></div></div></div><div id="ch37fisher.Protein_Expression_i"><h2 id="_ch37fisher_Protein_Expression_i_">Protein Expression in Cone Photoreceptors after Detachment: Analyzing the
Surviving Cone Photoreceptor Array</h2><p>What follows is a fairly detailed description of changes in the cone population after
detachment and reattachment as summarized in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12">Fig. 12</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a>. For those
who want to skip the details: cones appear to be lost from the retina after
detachment because they: 1) lose their outer segments; and 2) lose the expression of
specific proteins. Using the return of cone proteins as an indicator of cone
recovery after reattachment shows that at 28 days after reattachment, the cone
mosaic is not the same as in normal retinas. Both types of cones recover, although
the recovery of the S-cones may not be as complete as that of the M-cones. The
retinal cone mosaic is disturbed by detachment, and inconsistencies in its recovery
may account for visual defects after reattachment, especially if the fovea is
involved. There is nothing known about the recovery of the cone mosaics within the
fovea.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF13" co-legend-rid="figlgndch37fisherF13"><a href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" title="Figure 13" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13"><img class="small-thumb" src="/books/NBK11552/bin/fisherf13.gif" src-large="/books/NBK11552/bin/fisherf13.jpg" alt="Figure 13. Isodensity contours for short-wavelength sensitive (S)-cones labeled with an antibody to S-cone opsin in normal, detached, and reattached feline retinas." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF13"><h4 id="ch37fisher.F13"><a href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-ob="figobch37fisherF13">Figure 13</a></h4><p class="float-caption no_bottom_margin">Isodensity contours for short-wavelength sensitive (S)-cones
labeled with an antibody to S-cone opsin in normal, detached, and reattached
feline retinas. The greatest density of S-cones occurs in the inferior
retina in control retina. When the retina <a href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-ob="figobch37fisherF13">(more...)</a></p></div></div><p>As rod outer segments degenerate, rod opsin labeling begins to increase in the plasma
membrane of the cells until the whole cell is outlined (see <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F3/?report=objectonly" target="object" rid-figpopup="figch37fisherF3" rid-ob="figobch37fisherF3">Fig. 3</a>) (<a class="bk_pop" href="#ch37fisher.EXTYLES.24">24</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.42">42</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.43">43</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.53">53</a>).
Thus, antibodies to rod opsin can be used as markers for the presence of rod cells
(and the redistribution of labeling is also a remarkable indicator of stress or
injury to them). Although antibodies to the cone opsins begin to show a similar
redistribution (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F4/?report=objectonly" target="object" rid-figpopup="figch37fisherF4" rid-ob="figobch37fisherF4">Fig. 4</a>) after only
24 h of detachment, many cones fail to label with these antibodies (<a class="bk_pop" href="#ch37fisher.EXTYLES.53">53</a>). A similar
phenomenon occurs in retinas of humans with late-stage genetic degeneration (<a class="bk_pop" href="#ch37fisher.EXTYLES.62">62</a>).</p><p>Thus, markers for cones in the normal retina are not reliable for estimating the cone
population that survive detachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.52">52</a>). Indeed, if
the lack of labeled cones after detachment was an accurate reflection of cone
survival, then the effects of detachment on the cone population would be devastating
(<a class="bk_pop" href="#ch37fisher.EXTYLES.52">52</a>). Further
confounding the use of markers for cones is the fact that the response is not
consistent from marker to marker, nor even from one retinal region to another.</p><p>In the central region of a control retina, anti-calbindin D labels about 19,700
photoreceptors/mm<sup>2</sup>, and the antibody to S-cone opsin about
1,100/mm<sup>2</sup>. After 24 h of detachment, these numbers drop to
9,000/mm<sup>2</sup> (46% of control values) and 700/mm<sup>2</sup> (63% of
control values), respectively. By 28 days of detachment, there were no cells labeled
with the anti-calbindin D, but 200/mm<sup>2</sup> (18% of control values) labeled
with the anti-S-opsin (<a class="bk_pop" href="#ch37fisher.EXTYLES.52">52</a>) (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a>, B, and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-figpopup="figch37fisherF14" rid-ob="figobch37fisherF14">Fig. 14</a>, B-D). In
detached retinas, there are large areas in which no labeling appears at all with the
cone markers (see the example for PDEg in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F10/?report=objectonly" target="object" rid-figpopup="figch37fisherF10" rid-ob="figobch37fisherF10">Fig. 10</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F11/?report=objectonly" target="object" rid-figpopup="figch37fisherF11" rid-ob="figobch37fisherF11">Fig. 11</a>),
as if all of the cones in the region were gone. These dramatic changes are reflected
in the density maps for both S-opsin and anti-calbindin D labeling (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-figpopup="figch37fisherF14" rid-ob="figobch37fisherF14">Fig. 14</a>). In the latter, the central area is nearly
unrecognizable by 1 day of detachment and completely undefined after 3 days.
Similarly, the number of S-cones drops from between 700 and1,100/mm<sup>2</sup> in
the control retina to less than 300 in a 3-day detachment. Because of the relatively
large bins used to create these maps, they do not show the substantial islands in
which there were no labeled cones. The wide variations in numbers of labeled cones
gives the retinal wholemounts a "patchiness" that is not observed in control
retinas, where the transitions in cone density are smoothly graded.</p><p>We approached the question of cone survival in another way: by examining the recovery
of cone markers after reattachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.63">63</a>). We chose 3 days of detachment because
there is already a significant drop in the cone population labeled with peanut
agglutinin (PNA), anti-cone-opsin, or anti-calbindin D at that time. The superior
retina in the right eye of three animals was detached for 3 days and then reattached
for 28. The retinas were harvested and labeled with PNA (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12">Fig. 12</a>, PNA = all cones, only the superior temporal
quadrant is illustrated) and the antibody to S-opsin (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a>). Comparisons can be made to the maps for
total cones (calbindin D labeling, control and 3 days, <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F14/?report=objectonly" target="object" rid-figpopup="figch37fisherF14" rid-ob="figobch37fisherF14">Fig. 14</a>, A and C; PNA labeling, control retina,
<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12">Fig. 12</a>, A) and S-cones (S-cone
opsin labeling, control and 3 days, <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig.
13</a>, A and B). There is a recovery of both the PNA and S-cone population
after reattachment; indeed, a central-to-peripheral gradient is apparent in the PNA
labeling pattern, although the density remains depressed. None of the animals
recovered densities greater than 17,000-20,000 cones/mm<sup>2</sup> (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F12/?report=objectonly" target="object" rid-figpopup="figch37fisherF12" rid-ob="figobch37fisherF12">Fig. 12</a>, B-D). Similarly, the S-cone
population recovers, but recovery is not complete (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a>, C-E). The high density area of S-cones in
the far periphery of the superior-temporal quadrant is not recovered at 28 days of
reattachment, and in all three animals, recovery in the central retina was in the
range of 300-700 cells/mm<sup>2</sup>, compared with the 700-1,100
cells/mm<sup>2</sup> observed in the control retina (the detachment did not
extend into the yellow/red colored area in the central area of <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F13/?report=objectonly" target="object" rid-figpopup="figch37fisherF13" rid-ob="figobch37fisherF13">Fig. 13</a>, E).</p><p>Because these numbers are generated as counts from small sampling areas and the
contour lines on the maps drawn by eye, it is difficult to choose an average value
for cone density within the reattached retina, but using estimates of cone density
sampled over a fairly broad region, results from two animals with reattachments show
a recovery of 40-60% of PNA labeling in the area centralis and approaching 100%
recovery in the periphery.</p><p>S-cone recovery seems more variable, ranging between 0 and 40% with no pattern
readily discernable across the retina. Whereas PNA-labeled cone matrix sheaths were
remarkably evenly distributed across the retina and showed a central to peripheral
decline, S-opsin labeling showed large swatches within the reattached retinal map
with no visible labeling. These data demonstrate quantitatively that the absence of
marker molecules in the detached retinas does not indicate the absence of cone
photoreceptors, because cells recovered across the entire retina, in some cases to
numbers comparable with those in the control eyes. It is unknown, of course, if
there would be more recovery of these proteins over a longer reattachment time.</p><p>Structurally, the S-cone outer segments in the 28-day reattached retina are not
equivalent to those in the normal eye. They are often only punctate "dots," a
fraction of their normal size. The S-cone population has been reported to be more
sensitive to damage in human retinas with detachments (<a class="bk_pop" href="#ch37fisher.EXTYLES.64">64</a>) with all
S-cones either lost or showing signs of "irreversible damage" within a few days of
detachment. Our data from feline retinas may support the concept that S-cones are
more fragile, more susceptible to cell death, and slower to recover than the
M-cones; however, it does not support the conclusion that all of the S-cones are
irreversibly damaged.</p><p>Combined electrophysiological (ERG) and immunocytochemical studies in the
cone-dominant ground squirrel retina did not show any particular difference in
recovery of signals from S- and M/L-cones in that species (<a class="bk_pop" href="#ch37fisher.EXTYLES.65">65</a>).</p><p>What may be the most remarkable conclusion from this and other studies is that cones
appear to stop expressing specific proteins when the cells are under some type of
physiological stress, and then, at least in the case of reattachment, to begin
re-expressing these proteins as part of a recovery process. In their studies of
human retinal tissue, Nork et al. (<a class="bk_pop" href="#ch37fisher.EXTYLES.64">64</a>) reported
that carbonic anhydrase reactivity became an unreliable marker for M-cones after
detachment, indicating that it may join the list of severely down-regulated
proteins, and its loss may not be an indicator of irreversible damage.</p><p>Whether foveal cones show similar responses is an unanswered question. Peripheral
cones are structurally different from foveal cones in the primate retina (<a class="bk_pop" href="#ch37fisher.EXTYLES.33">33</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.66">66</a>),
so their reaction to injury and their capacity for recovery may differ as well.</p><p>A differential loss of M/L- and S-cones, or a differential recovery of these cells in
humans, may explain some of the color vision deficiencies reported in reattachment
patients and could underlie losses in visual acuity when the fovea is involved.</p></div><div id="ch37fisher.Remodeling_of_Photor"><h2 id="_ch37fisher_Remodeling_of_Photor_">Remodeling of Photoreceptors after Reattachment</h2><p>The fact that photoreceptor outer segments regrow after reattachment has been
recognized since 1968 (<a class="bk_pop" href="#ch37fisher.EXTYLES.67">67-69</a>).
This remarkable ability is mechanistically explained by the fact that photoreceptors
constantly add new outer segment material as part of the outer segment renewal
process (<a class="bk_pop" href="#ch37fisher.EXTYLES.70">70</a>). Thus, they
are poised to rebuild their outer segment as soon as favorable conditions allow.</p><p>Studies of detached retina in fact show that radiolabeled proteins continue to be
transported into the truncated outer segments of rods that degenerate after
detachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.43">43</a>), although
studies of rod-opsin, peripherin/rds (<a class="bk_pop" href="#ch37fisher.EXTYLES.42">42</a>) and ROM-1
(G.P. Lewis and S.K. Fisher, unpublished observations) distribution suggest that
protein targeting and trafficking is altered when the outer segment degenerates in
the rod cells.</p><p>There is some evidence from experimental data that the presence of opsin in the
plasma membrane may make photoreceptors more vulnerable to apoptotic cell death
(<a class="bk_pop" href="#ch37fisher.EXTYLES.71">71</a>).</p><p>The recovering rods appear structurally more like those in a normal retina than do
cones, which are often distorted in shape. Recovering primate cones also show
altered outer segment structure when observed by electron microscopy (<a class="bk_pop" href="#ch37fisher.EXTYLES.72">72</a>). It is now
recognized that vision may continue to recover over years in reattachment patients
(<a class="bk_pop" href="#ch37fisher.EXTYLES.73">73</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.74">74</a>), and this may
reflect a slow recovery of cone outer segments in the fovea. The recovery of cone
vision may be further complicated by the complex optical nature of cones and their
alignment with respect to the pupil (see the discussion in Rodieck (<a class="bk_pop" href="#ch37fisher.EXTYLES.75">75</a>) and also the
Stiles-Crawford effect (<a class="bk_pop" href="#ch37fisher.EXTYLES.76">76</a>)) (reviewed by Enoch (<a class="bk_pop" href="#ch37fisher.EXTYLES.77">77</a>) and Rodieck (<a class="bk_pop" href="#ch37fisher.EXTYLES.75">75</a>)), and their structurally specialized interface with the apical
RPE.</p><div id="ch37fisher.The_Recovery_of_Phot"><h3>The Recovery of Photoreceptor Synaptic Terminals</h3><p>The opposite pole of rod cells must also recover. Some recovery of the withdrawn
rod terminals occurs because after 1 month of reattachment, the outer border of
the OPL is again composed of a relatively compact layer of rod synaptic
terminals. This is in contrast to the highly disrupted layer occurring in the
detached retina (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5">Fig. 5</a>, compare
B to A). There have been no detailed structural, molecular, or physiological
analyses of these regenerated synapses.</p></div><div id="ch37fisher.Some_Rod_Axons_Overg"><h3>Some Rod Axons Overgrow</h3><p>Because some rods continue to express opsin in their plasma membrane after
reattachment, we were able to identify rod axons that extend well beyond the OPL
and into the inner retina, terminating at different levels in the INL and IPL
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F15/?report=objectonly" target="object" rid-figpopup="figch37fisherF15" rid-ob="figobch37fisherF15">Fig. 15</a>, B-D, arrowheads). The
endings of these "overgrown" axons also label with antibodies to the proteins
associated generally with synaptic vesicles, synaptophysin and VAMP (not shown),
but they do not express the ribbon-specific protein, ribeye.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF15" co-legend-rid="figlgndch37fisherF15"><a href="/books/NBK11552/figure/ch37fisher.F15/?report=objectonly" target="object" title="Figure 15" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF15" rid-ob="figobch37fisherF15"><img class="small-thumb" src="/books/NBK11552/bin/fisherf15.gif" src-large="/books/NBK11552/bin/fisherf15.jpg" alt="Figure 15. Labeling of RS and rod outer segments (ROS) in retinas detached for 3 days and reattached for 28." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF15"><h4 id="ch37fisher.F15"><a href="/books/NBK11552/figure/ch37fisher.F15/?report=objectonly" target="object" rid-ob="figobch37fisherF15">Figure 15</a></h4><p class="float-caption no_bottom_margin">Labeling of RS and rod outer segments (ROS) in retinas detached
for 3 days and reattached for 28. A, anti-synaptophysin labeling shows a
relative return of organization to the layer of synaptic terminals in the
OPL. The number of labeled terminals (arrowheads) <a href="/books/NBK11552/figure/ch37fisher.F15/?report=objectonly" target="object" rid-ob="figobch37fisherF15">(more...)</a></p></div></div><p>A population of rods also "overshoot" their synaptic target layer during early
retinal development, providing much the same picture as we observed in the
reattached retina (<a class="bk_pop" href="#ch37fisher.EXTYLES.78">78</a>), in human
retinas with advanced inherited retinal degeneration (<a class="bk_pop" href="#ch37fisher.EXTYLES.10">10</a>), and in
those with a history of complex detachments and reattachments (<a class="bk_pop" href="#ch37fisher.EXTYLES.30">30</a>). It is curious that
they do not seem to occur in the detached feline retinas, only appearing after
reattachment. The ectopic terminals have fine filopodia-like extensions (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F15/?report=objectonly" target="object" rid-figpopup="figch37fisherF15" rid-ob="figobch37fisherF15">Fig. 15</a>, C and D, arrowheads).
Whether the overgrown axons remain in place or are eventually retracted, or even
if the cells bearing them eventually die, is unknown for both development and
reattachment.</p></div><div id="ch37fisher.Remodeling_of_Cone_T"><h3>Remodeling of Cone Terminals after Reattachment</h3><p>To date, there is little data on the "redifferentiation" or remodeling of the
extraordinarily complex synapses of the cone terminals after reattachment. Cone
pedicles with synaptic invaginations do reappear in retinas detached for 3 days
and reattached for 28. In general, the redifferentiation of photoreceptor
synapses, along with profiles for the expression of specific pre- and
postsynaptic molecules after reattachment, is unexplored territory, but one that
seems critical to fully understanding the events related to visual recovery.</p></div></div><div id="ch37fisher.Remodeling_of_Second"><h2 id="_ch37fisher_Remodeling_of_Second_">Remodeling of Second- and Third-Order Neurons</h2><div id="ch37fisher.Rod_Bipolar_Cells"><h3>Rod Bipolar Cells</h3><p>Rod bipolar cells innervate the rod spherules. Each rod spherule is usually
presynaptic to two different rod bipolar cells, and each rod bipolar cell
contacts between 16 and 20 rod spherules (<a class="bk_pop" href="#ch37fisher.EXTYLES.79">79</a>). The rod
bipolar dendrites penetrate deeply into the invagination of the rod spherule to
terminate opposite one of the two (on average) synaptic ribbons (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F6/?report=objectonly" target="object" rid-figpopup="figch37fisherF6" rid-ob="figobch37fisherF6">Fig. 6</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F7/?report=objectonly" target="object" rid-figpopup="figch37fisherF7" rid-ob="figobch37fisherF7">Fig. 7</a>A) (<a class="bk_pop" href="#ch37fisher.EXTYLES.48">48</a>).</p><p>The general relationship between rod bipolar cells and rod spherules can be
observed by confocal imaging using antibodies (<a class="bk_pop" href="#ch37fisher.EXTYLES.80">80</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.81">81</a>) to label
each cell type (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16">Fig. 16</a>A). In the normal feline
retina, the compact layer of rod spherules stands out (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F5/?report=objectonly" target="object" rid-figpopup="figch37fisherF5" rid-ob="figobch37fisherF5">Fig. 5</a>A and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16">Fig. 16</a>A, green). Rod bipolar dendrites do not
extend beyond them into the ONL.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF16" co-legend-rid="figlgndch37fisherF16"><a href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" title="Figure 16" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16"><img class="small-thumb" src="/books/NBK11552/bin/fisherf16.gif" src-large="/books/NBK11552/bin/fisherf16.jpg" alt="Figure 16. Remodeling of RB cells after detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF16"><h4 id="ch37fisher.F16"><a href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-ob="figobch37fisherF16">Figure 16</a></h4><p class="float-caption no_bottom_margin">Remodeling of RB cells after detachment. In parts A-C, RB cells
are labeled with anti-protein kinase C (PKC, red) and photoreceptor synaptic
terminals with anti-synaptophysin (green). In parts D and E, only anti-PKC
labeling (green) is shown. A, dendrites <a href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-ob="figobch37fisherF16">(more...)</a></p></div></div></div><div id="ch37fisher.Rod_Bipolar_Dendrite"><h3>Rod Bipolar Dendrites Remodel as Rod Terminals Withdraw</h3><p>As the layer of rod terminals becomes disrupted after detachment, there is an
emergence of fine, tapered dendritic processes that reach from the rod bipolar
cells into the ONL, usually ending adjacent to withdrawn rod synaptic terminals
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16">Fig. 16</a>B, arrowheads).
Such remodeled dendritic branches are readily apparent within 3 days of a
detachment, and their number increases with detachment time.</p><p>There probably is also "pruning" of dendritic branches on these cells. In control
retinas, the dendrites appear as fine, "wispy" outgrowths extending from the
cell body into the OPL (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16">Fig.
16</a>D). In detached retinas, these are not nearly as prominent, leading to
the impression that some dendrites have withdrawn while others have grown in
length <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F16/?report=objectonly" target="object" rid-figpopup="figch37fisherF16" rid-ob="figobch37fisherF16">(Fig. 16</a>E). Pruning of
dendrites appears to be the major response of bipolar cells in other forms of
retinal degeneration (<a class="bk_pop" href="#ch37fisher.EXTYLES.13">13</a>), but in those cases the response appears late in the
diseases.</p></div><div id="ch37fisher.Horizontal_Cells"><h3>Horizontal Cells</h3><p>The feline retina has two morphologically distinct horizontal cells (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F17/?report=objectonly" target="object" rid-figpopup="figch37fisherF17" rid-ob="figobch37fisherF17">Fig.
17</a>): one with stout tapering dendrites and no axon (A-type), and the
other with somewhat finer, highly branched dendrites and a long thin axon that
forms an elaborate axon terminal (B-type) (<a class="bk_pop" href="#ch37fisher.EXTYLES.82">82</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.83">83</a>).
Electron microscopy demonstrated that the dendrites of both the A- and B-type
cells innervate the cone terminals, whereas only the branches of the axon
terminal innervate rod spherules (<a class="bk_pop" href="#ch37fisher.EXTYLES.49">49</a>). The thin
B-cell axon does not communicate electrically with the cell body (<a class="bk_pop" href="#ch37fisher.EXTYLES.84">84</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF17" co-legend-rid="figlgndch37fisherF17"><a href="/books/NBK11552/figure/ch37fisher.F17/?report=objectonly" target="object" title="Figure 17" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF17" rid-ob="figobch37fisherF17"><img class="small-thumb" src="/books/NBK11552/bin/fisherf17.gif" src-large="/books/NBK11552/bin/fisherf17.jpg" alt="Figure 17. Two types of horizontal cells in the feline retina." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF17"><h4 id="ch37fisher.F17"><a href="/books/NBK11552/figure/ch37fisher.F17/?report=objectonly" target="object" rid-ob="figobch37fisherF17">Figure 17</a></h4><p class="float-caption no_bottom_margin">Two types of horizontal cells in the feline retina. A, HA with a
dendritic spread of about 250 &#x003bc;m &#x000d7; 250
&#x003bc;m has no axon, and its dendrites contact only cone
photoreceptors. B, HB has a smaller dendritic field than HA (about 150
&#x003bc;m <a href="/books/NBK11552/figure/ch37fisher.F17/?report=objectonly" target="object" rid-ob="figobch37fisherF17">(more...)</a></p></div></div></div><div id="ch37fisher.Antibody_Labeling_Si"><h3>Antibody Labeling Signatures Define Horizontal Cell Subtypes</h3><p>Neurofilaments are plentiful in the A-type cell, and although not completely
absent, they are sparse in the B-type cell. This is reflected in the heavy
labeling of the A-type cell by antibodies to the 70- and 200-Kd subunits of the
neurofilament protein complex. Antibodies to the calcium binding proteins
calbindin D and calretinin also label horizontal cells. The use of these three
antibodies allowed us to differentiate the two subtypes in feline retina.</p><p>We initially observed fairly thick, beaded calbindin D-positive processes in the
ONL after detachment (red process, left of <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18">Fig. 18</a>A;
green processes, <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18">Fig. 18</a>C).
These outgrowths label with the antibody to neurofilament protein. Indeed, there
is a large increase in the intensity of horizontal cell labeling with this
antibody after detachment (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>, A and B, red, OPL), most
likely indicating an upregulation of protein expression in the remodeled cells
(<a class="bk_pop" href="#ch37fisher.EXTYLES.85">85</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF18" co-legend-rid="figlgndch37fisherF18"><a href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" title="Figure 18" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18"><img class="small-thumb" src="/books/NBK11552/bin/fisherf18.gif" src-large="/books/NBK11552/bin/fisherf18.jpg" alt="Figure 18. Horizontal cell remodeling after detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF18"><h4 id="ch37fisher.F18"><a href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-ob="figobch37fisherF18">Figure 18</a></h4><p class="float-caption no_bottom_margin">Horizontal cell remodeling after detachment. A and B, horizontal
cells (red) are labeled with anti-calbindin D and the synaptic terminals of
photoreceptors with anti-synaptophysin (green). Many fine red processes from
the horizontal cells extend into <a href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-ob="figobch37fisherF18">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF19" co-legend-rid="figlgndch37fisherF19"><a href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" title="Figure 19" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19"><img class="small-thumb" src="/books/NBK11552/bin/fisherf19.gif" src-large="/books/NBK11552/bin/fisherf19.jpg" alt="Figure 19. Horizontal cell remodeling after detachment seen by anti-neurofilament protein labeling (red)." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF19"><h4 id="ch37fisher.F19"><a href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-ob="figobch37fisherF19">Figure 19</a></h4><p class="float-caption no_bottom_margin">Horizontal cell remodeling after detachment seen by
anti-neurofilament protein labeling (red). Anti-GFAP (green) is used to
label Muller cells. A, normal retina. Prominent labeling with
anti-neurofilament of thick horizontal cell processes in the OPL, <a href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-ob="figobch37fisherF19">(more...)</a></p></div></div><p>Using any of these three antibodies, we can actually detect two types of
horizontal cell outgrowths: those that terminate adjacent to retracted rod
spherules (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18">Fig. 18</a>, A and B,
arrowheads), i.e., "directed" and those that do not, i.e., "undirected"
(examples in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18">Fig. 18</a>A, <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>B, and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig.
20</a>, D and E). Whether the strikingly dramatic "undirected" outgrowths
serve some functional or survival role for the horizontal cells or are merely
vestiges of an injury response is unknown. Amazingly, in detachments of 3 days
or longer, these outgrowths often extend beyond the outer limiting membrane and
into the subretinal space. This always occurs in conjunction with Muller cell
processes (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>, B and C,
green). Once in the subretinal space, the horizontal cell outgrowths (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>D, red) were never
observed growing on the exposed photoreceptor cells themselves but always
embedded within a meshwork of Muller cell processes (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>D, green), where they could run for long
distances.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF20" co-legend-rid="figlgndch37fisherF20"><a href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" title="Figure 20" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20"><img class="small-thumb" src="/books/NBK11552/bin/fisherf20.gif" src-large="/books/NBK11552/bin/fisherf20.jpg" alt="Figure 20. Remodeled horizontal cell processes probably arise from the axon terminal system of HB cells." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF20"><h4 id="ch37fisher.F20"><a href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-ob="figobch37fisherF20">Figure 20</a></h4><p class="float-caption no_bottom_margin">Remodeled horizontal cell processes probably arise from the axon
terminal system of HB cells. Labeling is with: anti-calretinin (red),
anti-calbindin D (blue), and anti-neurofilament (green). A and B, radial
sections, normal retina. HA have a "blue/white" <a href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-ob="figobch37fisherF20">(more...)</a></p></div></div></div><div id="ch37fisher.Horizontal_Cells_Ext"><h3>Horizontal Cells Extend Both Ascending and Descending Neuritis</h3><p>Some horizontal cell outgrowths are fairly thick processes descending from the
horizontal cells into the inner retina, although these were observed with much
less regularity than those ascending into the ONL. The descending processes were
also observed by Marc et al. (<a class="bk_pop" href="#ch37fisher.EXTYLES.13">13</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.86">86</a>) in the
detached feline retina and in other forms of retinal degeneration. Indeed, they
seem to be the most commonly encountered form of horizontal cell remodeling in
cases of extreme photoreceptor loss (<a class="bk_pop" href="#ch37fisher.EXTYLES.13">13</a>). The "undirected" ascending processes
in both sectioned material and wholemounts appear in two structural types: one
composed of thin, often beaded cylindrical processes, and the other as
flattened, ribbon-like processes. These can both occur singly and in clusters
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F18/?report=objectonly" target="object" rid-figpopup="figch37fisherF18" rid-ob="figobch37fisherF18">Fig. 18</a>C). Within the
subretinal space, the long extended processes all appear thin, cylindrical, and
often beaded (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>D). But,
when thicker, fleshier processes occur there, they usually branch profusely,
giving rise to complex assemblies reminiscent of sparse versions of axon
terminals of the B-type cell within the OPL (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig. 20</a>F).</p></div><div id="ch37fisher.The_Origin_of_the_Ho"><h3>The Origin of the Horizontal Cell Outgrowths</h3><p>By labeling with a combination of antibodies to neurofilament protein, calbindin
D, and calretinin and assigning the output colors as green, blue, and red,
respectively, we determined that the characteristically shaped A-type cells are
blue/white in color (i.e., heavily labeled with all three antibodies; HA in
<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig. 20</a>, A-C), whereas
cells with the appropriate shape and location to be the B-type are red or
near-red in color (because of the near lack of labeling with the
anti-neurofilament antibody; HB in <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig. 20</a>, B and C). The outgrowths into the ONL, including the long
processes that reach the subretinal space, all bear an immunochemical labeling
"signature" of the B-type cell (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig.
20</a>, D-F, arrows). When an outgrowth that gives rise to a branched
process in the subretinal space was traced back through the ONL, it was found to
arise from a complex plexus with an organization characteristic of the axon
terminal and with the B-type cell immunochemical signature (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F20/?report=objectonly" target="object" rid-figpopup="figch37fisherF20" rid-ob="figobch37fisherF20">Fig. 20</a>, D and E, arrows). Thus, the evidence
points to these processes as arising from the axon terminal of the B-type
horizontal cell (see the <a class="figpopup" href="/books/NBK11552/figure/A4403/?report=objectonly" target="object" rid-figpopup="figA4403" rid-ob="figobA4403">movie of horizontal
cell neurites growing out of a surrounding mass of Muller cells</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4403" co-legend-rid="figlgndA4403"><a href="/books/NBK11552/figure/A4403/?report=objectonly" target="object" title="Movie 1" class="img_link icnblk_img figpopup" rid-figpopup="figA4403" rid-ob="figobA4403"><img class="small-thumb" src="/books/NBK11552/bin/fishermv1.gif" src-large="/books/NBK11552/bin/fishermv1.jpg" alt="Movie 1. A movie of horizontal cell neurites (red) growing out of a surrounding mass of Muller cell processes (green) in a detached retina." /></a><div class="icnblk_cntnt" id="figlgndA4403"><h4 id="A4403"><a href="/books/NBK11552/figure/A4403/?report=objectonly" target="object" rid-ob="figobA4403">Movie 1</a></h4><p class="float-caption no_bottom_margin">A movie of horizontal cell
neurites (red) growing out of a surrounding mass of Muller cell
processes (green) in a detached retina. </p></div></div></div><div id="ch37fisher.What_Drives_the_Outg"><h3>What Drives the Outgrowth of Rod Bipolar and Horizontal Cell
Neurites?</h3><p>Although growth in response to the release (or lack) of some factor from the rods
is one possibility, another mechanism is suggested from studies of cultured
neurons in which mechanical tension can elicit neurite outgrowth (<a class="bk_pop" href="#ch37fisher.EXTYLES.87">87</a>). If the
rod bipolar cell dendrites and the horizontal cell axon terminal endings remain
mechanically connected to retracting rod spherules, tension generated by the
retracting rod spherules may initiate a growth response from the post-synaptic
neurons. Whether the same mechanism accounts for the generation of directed and
undirected outgrowths is unanswered.</p></div></div><div id="ch37fisher._Remodeling_of_Gangli"><h2 id="_ch37fisher__Remodeling_of_Gangli_">Remodeling of Ganglion Cells</h2><p>A subset of ganglion cell remodels vigorously in response to detachment. Ganglion
cells are the retinal neurons farthest removed from the site of the detachment. It
is important, however, to remember that ganglion cells are surrounded by Muller cell
processes, and the apical end of the Muller cells are in direct physical contact
with the actual site of the injury (the subretinal space). Muller cells also react
to detachment very quickly (<a class="bk_pop" href="#ch37fisher.EXTYLES.88">88</a>) and, thus,
could easily drive ganglion cell reactivity. Additionally, ganglion cell
responsiveness could be dependent on the trans-neuronal changes originating with
changes at the rod and cone synapses.</p><div id="ch37fisher.GAP_43_Expression__N"><h3>GAP 43 Expression, Neurofilament Protein Expression, and Ganglion Cell
Remodeling</h3><p>Growth associated protein (GAP 43) expression is generally associated with axonal
growth cones and synaptogenesis (<a class="bk_pop" href="#ch37fisher.EXTYLES.89">89-92</a>),
and it is generally down-regulated significantly after the developmental period
associated with synaptogenesis (<a class="bk_pop" href="#ch37fisher.EXTYLES.89">89-91</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.93">93-97</a>).
Mice in which GAP 43 has been genetically removed show a tangling of axons in
the optic nerve (<a class="bk_pop" href="#ch37fisher.EXTYLES.98">98</a>), whereas
mice overexpressing GAP 43 show an enhanced sprouting of axon terminals in both
central and peripheral neurons (<a class="bk_pop" href="#ch37fisher.EXTYLES.99">99</a>).</p><p>GAP 43 expression in the retina appears as the ganglion cells migrate into their
specific layer and begin the process of axon outgrowth. It remains in adults
only as stratified labeling in the IPL (<a class="bk_pop" href="#ch37fisher.EXTYLES.90">90</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.95">95</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.100">100-102</a>).
This is the pattern observed in the adult feline retina (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>).
Immunoblot analysis also reveals that there is some GAP 43 protein expressed in
normal adult feline retina (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>).</p><p>Immunoblot, immunocytochemical, and real-time PCR data all show a rise in GAP 43
expression beginning 1 day after a retinal detachment and continuing to increase
at the last experimental timepoint at 28 days. Immunohistochemistry data reveal
a population of ganglion cell bodies that are heavily labeled in the 7-day
postdetachment animals (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig. 21</a>A, red processes) (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>). The GAP
43-positive ganglion cells also show a major increase in labeling with the
anti-neurofilament protein antibody. In the normal retina, this antibody labels
only a few processes in the IPL and ganglion cell axons (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>A, red, IPL and GCL labeling) (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>). After
detachment, it heavily labels processes in the IPL and cell bodies in the
ganglion cell layer (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F19/?report=objectonly" target="object" rid-figpopup="figch37fisherF19" rid-ob="figobch37fisherF19">Fig. 19</a>B
and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig. 21</a>, B and C: red, IPL,
GCL labeling). This labeling colocalizes with the increased anti-neurofilament
labeling.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF21" co-legend-rid="figlgndch37fisherF21"><a href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" title="Figure 21" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21"><img class="small-thumb" src="/books/NBK11552/bin/fisherf21.gif" src-large="/books/NBK11552/bin/fisherf21.jpg" alt="Figure 21. Reactivity of ganglion cells to retinal detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF21"><h4 id="ch37fisher.F21"><a href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-ob="figobch37fisherF21">Figure 21</a></h4><p class="float-caption no_bottom_margin">Reactivity of ganglion cells to retinal detachment. A, anti-growth
associated protein 43 (GAP 43, red) labels only fine processes in the IPL of
normal adult retina. In retina detached for 28 days, anti-GAP 43 labels a
subpopulation of cell bodies in the <a href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-ob="figobch37fisherF21">(more...)</a></p></div></div></div><div id="ch37fisher.Ganglion_Cell_Morpho"><h3>Ganglion Cell Morphology after Detachment</h3><p>After detachment, the GAP 43/neurofilament-positive ganglion cells exhibit an
unusual morphology, unlike any reported in the literature for feline (or other
mammalian retinas) ganglion cells, with numerous small, spikey processes
extending from their cell body toward the nerve fiber layer (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig. 21</a>C) (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>). As
detachment duration increases, there is an astonishing increase in GAP
43/neurofilament-positive neurites that extend from the labeled ganglion cells
and course completely across the neural retina and into the subretinal space
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig. 21</a>, B and C, arrows).
These processes are generally of a uniform caliber without obvious
branching.</p></div><div id="ch37fisher._Remodeling_of_Gangli_1"><h3>Remodeling of Ganglion Cells Is "Extreme"</h3><p>Thus, the picture that emerges for remodeled ganglion cells is very much like
that of the remodeled horizontal cell axon terminals, inasmuch as both produce a
large number of "undirected" processes that can grow for long distances through
the retina and into the subretinal space. The neurites from ganglion cells also
tend to appear adjacent to the processes of reactive Muller cells, either within
the retina or in the subretinal space. Interestingly, neuronal processes have
been identified in subretinal membranes removed surgically from human eyes (G.P.
Lewis and S.K. Fisher, unpublished observations).</p></div><div id="ch37fisher.Which_Ganglion_Cell_"><h3>Which Ganglion Cell Type(s) Remodels?</h3><p>Size measurements from retinal wholemounts were used to produce a frequency
distribution for the somal area of the GAP 43-labeled ganglion cells. The data
show a large peak at 600 &#x003bc;m<sup>2</sup> but also a small population
of cells clustering around 3,000 &#x003bc;m<sup>2</sup> (<a class="bk_pop" href="#ch37fisher.EXTYLES.18">18</a>),
suggesting that it is the alpha ganglion cell types (<a class="bk_pop" href="#ch37fisher.EXTYLES.103">103</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.104">104</a>) that
remodel.</p></div><div id="ch37fisher.Ganglion_Cell_Remode"><h3>Ganglion Cell Remodeling after Reattachment</h3><p>Retinal reattachment appears to elicit the extensive growth of ganglion cell
neurites into the vitreous, where they associate with epiretinal membranes
produced by Muller cells (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig.
21</a>C, arrows; <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F21/?report=objectonly" target="object" rid-figpopup="figch37fisherF21" rid-ob="figobch37fisherF21">Fig.
21</a>D, arrowheads). Thus, the response in the vitreous is similar to the
response in the subretinal space; neurite outgrowths associate with reactive
Muller cell processes, but the vitreal growth is initiated only after
reattachment, probably because reattachment also initiates the growth of Muller
cells into the vitreous cavity (<a class="bk_pop" href="#ch37fisher.EXTYLES.105">105</a>). Data
from pathology specimens of human vitreal membranes also show the presence of
anti-neurofilament labeled processes (<a class="bk_pop" href="#ch37fisher.EXTYLES.30">30</a>).</p></div></div><div id="ch37fisher.Glial_Cell_Remodelin"><h2 id="_ch37fisher_Glial_Cell_Remodelin_">Glial Cell Remodeling</h2><div id="ch37fisher.Muller_Cells"><h3>Muller Cells</h3><p>Muller cells undergo extensive hypertrophy after detachment. They also show
nuclear migration, cell division, and growth into the subretinal space. All of
these are obvious by simple histological observation (<a class="bk_pop" href="#ch37fisher.EXTYLES.14">14</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.15">15</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.39">39</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.69">69</a>).</p></div><div id="ch37fisher.The_Intermediate_Fil"><h3>The Intermediate Filament Cytoskeleton and Remodeling</h3><p>The structural hypertrophy of these cells correlates with increased expression of
intermediate filament proteins, glial fibrillary acidic protein (GFAP), and
vimentin (<a class="bk_pop" href="#ch37fisher.EXTYLES.106">106</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.107">107</a>).
Electron microscopy also shows a large increase in the number of intermediate
filaments in the cytoplasm of these reactive cells (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F22/?report=objectonly" target="object" rid-figpopup="figch37fisherF22" rid-ob="figobch37fisherF22">Fig. 22</a>)
(<a class="bk_pop" href="#ch37fisher.EXTYLES.108">108</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF22" co-legend-rid="figlgndch37fisherF22"><a href="/books/NBK11552/figure/ch37fisher.F22/?report=objectonly" target="object" title="Figure 22" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF22" rid-ob="figobch37fisherF22"><img class="small-thumb" src="/books/NBK11552/bin/fisherf22.gif" src-large="/books/NBK11552/bin/fisherf22.jpg" alt="Figure 22. 10-nm-diameter filaments in the cytoplasm of a Muller cell in the outer retina after retinal detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF22"><h4 id="ch37fisher.F22"><a href="/books/NBK11552/figure/ch37fisher.F22/?report=objectonly" target="object" rid-ob="figobch37fisherF22">Figure 22</a></h4><p class="float-caption no_bottom_margin">10-nm-diameter filaments in the cytoplasm of a Muller cell in the
outer retina after retinal detachment. These intermediate filaments label
with antibodies to both GFAP and vimentin. In the normal retina, they are
mainly limited to the endfoot region <a href="/books/NBK11552/figure/ch37fisher.F22/?report=objectonly" target="object" rid-ob="figobch37fisherF22">(more...)</a></p></div></div><p>Astrocytes in the brain and spinal cord react similarly, especially with respect
to an upregulation of GFAP (<a class="bk_pop" href="#ch37fisher.EXTYLES.14">14</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.109">109</a>).</p></div><div id="ch37fisher.The_Muller_Cell_Resp"><h3>The Muller Cell Response Is Distinct and Dramatic</h3><p>What makes the Muller cell GFAP response so dramatic is the fact that these
filamentous proteins are almost exclusively localized to the endfoot region in a
normal retina (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-figpopup="figch37fisherF23" rid-ob="figobch37fisherF23">Fig. 23</a>A, red/yellow labeling)
and, in some species such as rats and mice, barely detectable by current
immunocytochemical technology (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-figpopup="figch37fisherF23" rid-ob="figobch37fisherF23">Fig.
23</a>C) (<a class="bk_pop" href="#ch37fisher.EXTYLES.110">110-112</a>).
On injury, the cytoskeletal remodeling in these cells correlates closely with
changes in morphology. Indeed, the correlation is so close that they are
generally assumed to be functionally linked events. In support of this argument
is the fact that in the ground squirrel retina, Muller cells do not hypertrophy
in response to detachment, and their intermediate filament cytoskeleton remains
unchanged (<a class="bk_pop" href="#ch37fisher.EXTYLES.24">24</a>). Following
brain injury, astrocytic scar formation is impaired in
vim<sup>-/-</sup>/GFAP<sup>-/-</sup> mice but not in mice lacking only one
of the two intermediate filament genes (<a class="bk_pop" href="#ch37fisher.EXTYLES.113">113</a>). Whether
a similar principle applies to Muller cells remains to be determined.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF23" co-legend-rid="figlgndch37fisherF23"><a href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" title="Figure 23" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF23" rid-ob="figobch37fisherF23"><img class="small-thumb" src="/books/NBK11552/bin/fisherf23.gif" src-large="/books/NBK11552/bin/fisherf23.jpg" alt="Figure 23. Labeling with antibodies to the intermediate filament proteins GFAP (green) and vimentin (red)." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF23"><h4 id="ch37fisher.F23"><a href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-ob="figobch37fisherF23">Figure 23</a></h4><p class="float-caption no_bottom_margin">Labeling with antibodies to the intermediate filament proteins
GFAP (green) and vimentin (red). A, in the normal retina, they are
concentrated in the endfoot region of the Muller cells. Vimentin
predominates over GFAP (astrocytes, however, show a preponderance <a href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-ob="figobch37fisherF23">(more...)</a></p></div></div></div><div id="ch37fisher.The_Muller_Cell_Endf"><h3>The Muller Cell Endfoot as the Origin of the Intermediate Filament
Response</h3><p>Within a day of a detachment, intermediate filament proteins within the endfoot
become more dense in number, often forming whorl-like or wavy bundles (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-figpopup="figch37fisherF23" rid-ob="figobch37fisherF23">Fig. 23</a>B, red/yellow labeling)
(<a class="bk_pop" href="#ch37fisher.EXTYLES.108">108</a>). They
appear to grow from this distal mass, extending both into branches of the
endfoot, which increase in size and in number with detachment time, and apically
towards the cell body and then into the outer retina (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F23/?report=objectonly" target="object" rid-figpopup="figch37fisherF23" rid-ob="figobch37fisherF23">Fig. 23</a> and <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F24/?report=objectonly" target="object" rid-figpopup="figch37fisherF24" rid-ob="figobch37fisherF24">Fig. 24</a>)
(<a class="bk_pop" href="#ch37fisher.EXTYLES.107">107</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.114">114</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF24" co-legend-rid="figlgndch37fisherF24"><a href="/books/NBK11552/figure/ch37fisher.F24/?report=objectonly" target="object" title="Figure 24" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF24" rid-ob="figobch37fisherF24"><img class="small-thumb" src="/books/NBK11552/bin/fisherf24.gif" src-large="/books/NBK11552/bin/fisherf24.jpg" alt="Figure 24. Retinal flat-mounts labeled with antibodies to GFAP (green) and vimentin (red) viewed from the ganglion cell surface to show changes in the Muller cell endfeet after detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF24"><h4 id="ch37fisher.F24"><a href="/books/NBK11552/figure/ch37fisher.F24/?report=objectonly" target="object" rid-ob="figobch37fisherF24">Figure 24</a></h4><p class="float-caption no_bottom_margin">Retinal flat-mounts labeled with antibodies to GFAP (green) and
vimentin (red) viewed from the ganglion cell surface to show changes in the
Muller cell endfeet after detachment. A, normal retina. The endfeet are
"hoof-shaped", and their labeling is dominated <a href="/books/NBK11552/figure/ch37fisher.F24/?report=objectonly" target="object" rid-ob="figobch37fisherF24">(more...)</a></p></div></div></div><div id="ch37fisher.Subretinal_Growth_of"><h3>Subretinal Growth of Muller Cells after Detachment</h3><p>As intermediate filaments expand into the apical cytoplasm of the activated
Muller cells, some of them begin to grow, expanding into the subretinal space
where they can elaborate into multilayered clinical "membranes" (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" rid-figpopup="figch37fisherF25" rid-ob="figobch37fisherF25">Fig.
25</a>, A and B).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF25" co-legend-rid="figlgndch37fisherF25"><a href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" title="Figure 25" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF25" rid-ob="figobch37fisherF25"><img class="small-thumb" src="/books/NBK11552/bin/fisherf25.gif" src-large="/books/NBK11552/bin/fisherf25.jpg" alt="Figure 25. The subretinal space in retinal flat-mounts prepared after detachment and labeled with antibodies to vimentin (red) and GFAP (green)." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF25"><h4 id="ch37fisher.F25"><a href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" rid-ob="figobch37fisherF25">Figure 25</a></h4><p class="float-caption no_bottom_margin">The subretinal space in retinal flat-mounts prepared after
detachment and labeled with antibodies to vimentin (red) and GFAP (green).
A, retina detached for 3 days. Initial outgrowth of a Muller cell process
(red) from the neural retina into the subretinal <a href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" rid-ob="figobch37fisherF25">(more...)</a></p></div></div></div><div id="ch37fisher.GFAP_and_Vimentin_De"><h3>GFAP and Vimentin: Details of Their Responses in the Muller Cells Subretinal
Space</h3><p>GFAP and vimentin can copolymerize to form intermediate filaments, but we have
observed in double-labeling studies that there is a differential expression of
the two in feline Muller cells. In the normal retina, vimentin predominates. The
endfeet label most heavily with this antibody, and labeling extends farther into
the neural retina than it does for GFAP. In the main trunk of the reactive
cells, GFAP seems to predominate. As the apical microvilli begin to grow into
the subretinal space, vimentin labeling predominates (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" rid-figpopup="figch37fisherF25" rid-ob="figobch37fisherF25">Fig. 25</a>A, red tapering forked processes). This
imbalance in expression continues as the processes expand into the subretinal
space (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F25/?report=objectonly" target="object" rid-figpopup="figch37fisherF25" rid-ob="figobch37fisherF25">Fig. 25</a>B) (<a class="bk_pop" href="#ch37fisher.EXTYLES.114">114</a>). The "leading edge"
of the growing processes always shows a predominance of anti-vimentin labeling,
with GFAP expression becoming increasingly intense at the point of exit from the
neural retina. These processes or "membranes" essentially form glial scars in
the subretinal space. Their presence does not appear to prevent physical
reattachment of the retina, but it does inhibit the regeneration of outer
segments (<a class="bk_pop" href="#ch37fisher.EXTYLES.39">39</a>) (see the
<a class="figpopup" href="/books/NBK11552/figure/A4404/?report=objectonly" target="object" rid-figpopup="figA4404" rid-ob="figobA4404">movie of Muller cell processes growing out
into subretinal space</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4404" co-legend-rid="figlgndA4404"><a href="/books/NBK11552/figure/A4404/?report=objectonly" target="object" title="Movie 2" class="img_link icnblk_img figpopup" rid-figpopup="figA4404" rid-ob="figobA4404"><img class="small-thumb" src="/books/NBK11552/bin/fishermv2.gif" src-large="/books/NBK11552/bin/fishermv2.jpg" alt="Movie 2. A movie of Muller cell processes (green) growing out into subretinal space in a detached retina." /></a><div class="icnblk_cntnt" id="figlgndA4404"><h4 id="A4404"><a href="/books/NBK11552/figure/A4404/?report=objectonly" target="object" rid-ob="figobA4404">Movie 2</a></h4><p class="float-caption no_bottom_margin">A movie of Muller cell
processes (green) growing out into subretinal space in a detached
retina. </p></div></div></div><div id="ch37fisher.Reattachment_Stimula"><h3>Reattachment Stimulates Growth of Muller Cells</h3><div id="ch37fisher.Vitreous_Space"><h4>Vitreous Space</h4><p>A novel endfoot response occurs in the feline retina in response to
reattachment. In this case, the branched endfoot processes that remained
closely adherent to the vitreal surface of the retina begin growing into the
vitreous chamber. It is these "branchlets" of the endfoot that expand into
the vitreous to form epiretinal membranes. The initial outgrowths appear as
fine, flat "ribbons" of cytoplasm extending away from the neural retina into
the vitreous cavity (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" rid-figpopup="figch37fisherF26" rid-ob="figobch37fisherF26">Fig. 26</a>, A and B) (see the
<a class="figpopup" href="/books/NBK11552/figure/A4406/?report=objectonly" target="object" rid-figpopup="figA4406" rid-ob="figobA4406">movie of Muller cell endfeet growing
out into the vitreous</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF26" co-legend-rid="figlgndch37fisherF26"><a href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" title="Figure 26" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF26" rid-ob="figobch37fisherF26"><img class="small-thumb" src="/books/NBK11552/bin/fisherf26.gif" src-large="/books/NBK11552/bin/fisherf26.jpg" alt="Figure 26. The vitreal surface of retinal flat-mounts prepared after the retinas were detached for 3 days and reattached for 28 days and labeled with antibodies to vimentin (red) and GFAP (green)." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF26"><h4 id="ch37fisher.F26"><a href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" rid-ob="figobch37fisherF26">Figure 26</a></h4><p class="float-caption no_bottom_margin">The vitreal surface of retinal flat-mounts prepared after the
retinas were detached for 3 days and reattached for 28 days and labeled with
antibodies to vimentin (red) and GFAP (green). A, high magnification image
of the retinal surface. The Muller cell <a href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" rid-ob="figobch37fisherF26">(more...)</a></p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4406" co-legend-rid="figlgndA4406"><a href="/books/NBK11552/figure/A4406/?report=objectonly" target="object" title="Movie 3" class="img_link icnblk_img figpopup" rid-figpopup="figA4406" rid-ob="figobA4406"><img class="small-thumb" src="/books/NBK11552/bin/fishermv3.gif" src-large="/books/NBK11552/bin/fishermv3.jpg" alt="Movie 3. A movie of Muller cell endfeet (green) growing out into the vitreous in a detached retina." /></a><div class="icnblk_cntnt" id="figlgndA4406"><h4 id="A4406"><a href="/books/NBK11552/figure/A4406/?report=objectonly" target="object" rid-ob="figobA4406">Movie 3</a></h4><p class="float-caption no_bottom_margin">A movie of Muller cell
endfeet (green) growing out into the vitreous in a detached
retina. </p></div></div><p>These delicate, flattened processes have a very different morphology from the
fine, tapered, and branched processes that expand into the subretinal space.
In these endfoot outgrowths, GFAP expression dominates over that of vimentin
(<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" rid-figpopup="figch37fisherF26" rid-ob="figobch37fisherF26">Fig. 26</a>, A and B).
Although vimentin expression "leads the way" in the expanding Muller cell
processes within the subretinal space, it is GFAP that holds this position
in the endfoot processes that grow into the vitreous (<a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F26/?report=objectonly" target="object" rid-figpopup="figch37fisherF26" rid-ob="figobch37fisherF26">Fig. 26</a>, C and D). The growth of these
cellular processes into the vitreous can have significant consequences on
vision because they can become contractile (<a class="bk_pop" href="#ch37fisher.EXTYLES.115">115</a>) and
cause wrinkling and eventual re-detachment of the neural
retina&#x02014;a serious sight-threatening event if the fovea is
involved.</p></div><div id="ch37fisher.Astrocytes"><h4>Astrocytes</h4><p>There is little known about the reactive capacity of these cells in the
retina. They proliferate in response to detachment (<a class="bk_pop" href="#ch37fisher.EXTYLES.116">116</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.117">117</a>),
and observations of optic nerve fiber layer in retinal wholemounts show that
their regular array and stellate shape are lost as the endfeet of the Muller
cells expand on the retinal surface (<a class="bk_pop" href="#ch37fisher.EXTYLES.114">114</a>).</p></div></div></div><div id="ch37fisher.Retinal_Remodeling_a"><h2 id="_ch37fisher_Retinal_Remodeling_a_">Retinal Remodeling after Detachment and Reattachment: An Overview</h2><p>Studies of detached (and reattached) retina have shown us that the mammalian retina
has remarkable remodeling capabilities. <a class="figpopup" href="/books/NBK11552/figure/ch37fisher.F27/?report=objectonly" target="object" rid-figpopup="figch37fisherF27" rid-ob="figobch37fisherF27">Fig. 27</a> shows, in summary form, the
remodeling of the neural retina described here.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figch37fisherF27" co-legend-rid="figlgndch37fisherF27"><a href="/books/NBK11552/figure/ch37fisher.F27/?report=objectonly" target="object" title="Figure 27" class="img_link icnblk_img figpopup" rid-figpopup="figch37fisherF27" rid-ob="figobch37fisherF27"><img class="small-thumb" src="/books/NBK11552/bin/fisherf27.gif" src-large="/books/NBK11552/bin/fisherf27.jpg" alt="Figure 27. A drawing summarizing the remodeling events in the feline retina as a result of detachment." /></a><div class="icnblk_cntnt" id="figlgndch37fisherF27"><h4 id="ch37fisher.F27"><a href="/books/NBK11552/figure/ch37fisher.F27/?report=objectonly" target="object" rid-ob="figobch37fisherF27">Figure 27</a></h4><p class="float-caption no_bottom_margin">A drawing summarizing the remodeling events in the feline retina
as a result of detachment. A, astrocytes; atB, axon terminal of B-type
horizontal cell; C, cone; COS, cone outer segments; G, ganglion cells; HB,
B-type horizontal cells; M, Muller cells; <a href="/books/NBK11552/figure/ch37fisher.F27/?report=objectonly" target="object" rid-ob="figobch37fisherF27">(more...)</a></p></div></div><p>Rod outer segments and cone outer segments are greatly shortened and separated from
the apical surface of the pigmented epithelium. Many RS are withdrawn from the OPL.
After reattachment, some rod axons grow into the inner retina (the cell on the
left). CP remain in place, although they undergo significant structural remodeling.
The dendrites of RB cells grow into the ONL, where they terminate adjacent to
withdrawn RS. The axon terminals of HB remodel extensively, with some processes
terminating next to withdrawn RS, whereas others grow wildly into the outer retina
and into the subretinal space adjacent to reactive Muller cells. HB axon terminals
can also grow into the inner retina, although this reaction appears less frequently.
A subpopulation of ganglion cells extend short, spikey neurites from their base
after and can also grow processes into the outer retina, where they behave much like
the neurites of horizontal cells. In the reattached retinas, ganglion cell processes
can also grow into epiretinal membranes formed by Muller cell growth into the
vitreous. Muller cells are highly reactive to detachment and grow in the subretinal
space to form membranes or glial scars on the exposed photoreceptor OS. After
detachment, their endfeet expand but remain within the ILM. After reattachment,
their specialized endfeet can grow into the vitreous to form epiretinal membranes as
part of the disease, proliferative vitreoretinopathy. Astrocytes proliferate and
often appear in epiretinal membranes, but their responses to detachment have not
been characterized in detail.</p><p>Muller cell changes may occur in response to photoreceptor cell deconstruction and/or
cell death or they may arise independently. Although it would seem logical that the
remodeling changes in second-order neurons would be signaled from photoreceptor
changes and remodeling of third-order neurons signaled by changes in bipolar cells,
this has not been proven experimentally.</p></div><div id="ch37fisher.Future_Challenges"><h2 id="_ch37fisher_Future_Challenges_">Future Challenges</h2><p>Data from the detachment model, as well as from a variety of other studies, now
suggests that retinal neurons remain capable of significant structural remodeling in
adult mammals. This in turn may provide increased optimism for a variety of
therapies for blinding diseases in which photoreceptor degeneration is the primary
cause of visual loss. Although preventing photoreceptor cell death is the optimum
therapy in these diseases, alternatives to this daunting challenge include
technology for replacing photoreceptors, whether it is by way of cellular
transplantation (<a class="bk_pop" href="#ch37fisher.EXTYLES.118">118</a>) or the use of
progenitor cells (<a class="bk_pop" href="#ch37fisher.EXTYLES.119">119-121</a>). This
success, however, would be hollow if the second-order neurons did not retain
sufficient plasticity to form functional connections with the new photoreceptors. It
may seem far-fetched at the present that such connections would form circuitry for
functional vision. However, the degree of remodeling we have observed may be an
indicator that the inner retina has more of a capacity for remodeling itself than
previously imagined. Studies of patients with foveal
reattachments&#x02014;indicating that visual recovery may occur over years, not
weeks&#x02014;could conceivably represent the re-formation of appropriately
functional retinal circuits, or even a remodeling of the RPE/photoreceptor interface
to properly align the foveal cones. In the case of detachment, preventing both
photoreceptor and Muller cell reactivity may also be key to treating the injury and
preventing threats to sight through diseases such as subretinal fibrosis and
proliferative vitreoretinopathy. Adjuncts to therapy do not seem so distant in these
cases, because treatment with something as simple as elevated oxygen concentration
appears to help attain these goals in animal models (<a class="bk_pop" href="#ch37fisher.EXTYLES.25">25</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.40">40</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.47">47</a>, <a class="bk_pop" href="#ch37fisher.EXTYLES.122">122</a>).</p></div><div id="ch37fisher.AFN1"><h2 id="_ch37fisher_AFN1_">About the Author</h2><p>
<div class="graphic"><img src="/books/NBK11552/bin/fisherfu1.jpg" alt="Image fisherfu1.jpg" /></div>
Dr. Steven Fisher was born in a small farm village in
northern Indiana. He received his B.S. (Experimental Psychology, 1964), M.S.
(Physiology, 1966), and Ph.D. (Neurobiology, 1969) degrees from Purdue
University. His mentor for the Ph.D. was (the late) Professor Marcus
Jacobson. Steve then did an NIH Postdoctoral Fellowship in 1969 in the
laboratory of Dr. John Dowling at the Wilmer Institute. His first academic
appointment was in 1971 as an Assistant Professor of Biology at the
University of California, Santa Barbara. He remains at UCSB as Professor of
Molecular Cellular and Developmental Biology and a member of the
Neuroscience Research Institute. He was the founding Director of that
Institute. His research interests include the organization of the vertebrate
retina, the cell biology of retinal injury regeneration within the retina.
Recently, he has moved into the world of bio-image informatics, and he is
now part of the Center for BioImage Informatics at UCSB (<a href="http://www.bioimage.ucsb.edu" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">http://www.bioimage.ucsb.edu/</a>). The NSF-supported Center has
as its mission the building of large, distributed, searchable databases of
biological tissue and the building of special tools for the analysis of
biological images. He has been honored with a Research Career Development
Award and a M.E.R.I.T. Award from the National Eye Institute, and in 2002
with the Ludwig Von Sallmann Prize for Vision Research.</p></div><div id="ch37fisher.References"><h2 id="_ch37fisher_References_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.1">Dowling JE. Organization of vertebrate retinas. <span><span class="ref-journal">Invest Ophthalmol. </span>1970;<span class="ref-vol">9</span>:655–680.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/4915972" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 4915972</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.2">Kolb H, Famiglietti EV. Rod and cone pathways in the retina of the cat. <span><span class="ref-journal">Invest Ophthalmol. </span>1976;<span class="ref-vol">15</span>:935–946.</span></div></dd><dt>3.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.3">Kolb H, Nelson R, Ahnelt P, Cuenca N. Cellular
organization of the vertebrate retina. In: Kolb H, Ripps H, Wu S, editors. Prog.
Brain Res. 131. Concepts and challenges in retinal biology. A tribute to John E.
Dowling. Amsterdam: Elsevier; 2001. p. 3-26. [<a href="https://pubmed.ncbi.nlm.nih.gov/11420950" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11420950</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.4">Linberg K, Cuenca N, Ahnelt P, Fisher S, Kolb H.
(2001). Comparative anatomy of major retinal pathways in the eyes of nocturnal
and diurnal mammals. In: Kolb H, Ripps H, Wu S, editors. Concepts and challenges
in retinal biology. A tribute to John E. Dowling. Prog Brain Res. 131:
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circadian rhythm? In: Ali MA, editor. Vision in fishes: new approaches in
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679-686.</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.6">Wagner H-J, Ali MA. Cone synaptic ribbons and retinomotor changes in the brook trout,
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terminals in cone pedicles of fish retinas. <span><span class="ref-journal">J Neurocytol. </span>1980;<span class="ref-vol">9</span>:573–590.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7441304" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7441304</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.8">Peichl L, Bolz J. Kainic acid induces sprouting of retinal neurons. <span><span class="ref-journal">Science. </span>1984;<span class="ref-vol">223</span>:503–504.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6691162" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6691162</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.9">Chu Y, Humphrey MF, Constable IJ. Horizontal cells of the normal and dystrophic rat retina: a
wholemount study using immunolabeling for the 28 kDa calcium binding
protein. <span><span class="ref-journal">Exp Eye Res. </span>1993;<span class="ref-vol">57</span>:141–148.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8405180" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 8405180</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.10">Fariss RN, Li ZY, Milam AH. Abnormalities in rod photoreceptors, amacrine cells, and
horizontal cells in humans with retinitis pigmentosa. <span><span class="ref-journal">Am J Ophthalmol. </span>2000;<span class="ref-vol">129</span>:215–223.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10682975" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10682975</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.11">Lewis GP, Linberg KA, Fisher SK. Neurite outgrowth from bipolar and horizontal cells following
experimental retinal detachment. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1998;<span class="ref-vol">39</span>:424–434.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9478003" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 9478003</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.12">Li ZY, Kljavin IJ, Milam AH. Rod photoreceptor neurite sprouting in retinitis
pigmentosa. <span><span class="ref-journal">J Neurosci. </span>1995;<span class="ref-vol">15</span>:5429–5438.</span> [<a href="/pmc/articles/PMC6577619/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6577619</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7643192" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7643192</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.13">Marc RE, Jones BW, Watt CB, Strettoi E. Neural remodeling in retinal degeneration. <span><span class="ref-journal">Prog Retin Eye Res. </span>2003;<span class="ref-vol">22</span>:607–655.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12892644" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12892644</span></a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.14">Anderson DH, Stern WH, Fisher SK, Erickson PA, Borgula GA. Retinal detachment in the cat: the pigment
epithelial-photoreceptor interface. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1983;<span class="ref-vol">24</span>:906–926.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6862795" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6862795</span></a>]</div></dd><dt>15.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.15">Erickson PA, Fisher SK, Anderson DH, Stern WH, Borgula GA. Retinal detachment in the cat: the outer nuclear and outer
plexiform layers. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1983;<span class="ref-vol">24</span>:927–942.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6862796" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6862796</span></a>]</div></dd><dt>16.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.16">Kroll AJ, Machemer R. Experimental retinal detachment in the owl monkey. III. Electron
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retinal degeneration induced by retinal detachment. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1995;<span class="ref-vol">36</span>:2404–2416.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7591630" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7591630</span></a>]</div></dd><dt>108.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.108">Erickson PA, Fisher SK, Gurin CJ, Anderson DH, Kaska DD. Glial fibrillary acidic protein increases in Muller cells after
retinal detachment. <span><span class="ref-journal">Exp Eye Res. </span>1987;<span class="ref-vol">44</span>:37–48.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3549345" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 3549345</span></a>]</div></dd><dt>109.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.109">Eng LF, DeArmond SJ. 1981. </div></dd><dt>110.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.110">Bignami A, Dahl D. The radial glia of Muller in the rat retina and their response to
injury. An immunofluorescence study with antibodies to the glial fibrillary
acidic (GFA) protein. <span><span class="ref-journal">Exp Eye Res. </span>1979;<span class="ref-vol">28</span>:63–69.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/376324" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 376324</span></a>]</div></dd><dt>111.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.111">Eisenfeld AJ, Bunt-Milam AH, Sarthy PV. Muller cell expression of glial fibrillary acidic protein after
genetic and experimental photoreceptor degeneration in the rat
retina. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1984;<span class="ref-vol">25</span>:1321–1328.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6386743" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6386743</span></a>]</div></dd><dt>112.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.112">Sarthy V, Ripps H. The retinal Muller cell. In:
Blakemore C, editor. Perspectives in vision research. New York: Plenum Press;
2001.</div></dd><dt>113.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.113">Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold C-H, Frisen J. Abnormal reaction to central nervous system injury in mice
lacking glial fibrillary acidic protein and vimentin. <span><span class="ref-journal">J Cell Biol. </span>1999;<span class="ref-vol">145</span>:503–514.</span> [<a href="/pmc/articles/PMC2185074/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC2185074</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10225952" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10225952</span></a>]</div></dd><dt>114.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.114">Lewis GP, Fisher SK. 2003. Upregulation of GFAP
in response to retinal injury: Its potential role in glial remodeling and a
comparison to vimentin expression. In: K.W. Jeon, editor. Int. Rev. Cytol. A
Survey of Cell Biology. Vol. 230. San Diego (CA): Elsevier Academic Press; 2003.
p. 263-290. [<a href="https://pubmed.ncbi.nlm.nih.gov/14692684" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 14692684</span></a>]</div></dd><dt>115.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.115">Ryan SJ. The pathophysiology of proliferative vitreoretinopathy in its
mangagement. <span><span class="ref-journal">Am J Ophthalmol. </span>1985;<span class="ref-vol">100</span>:188–193.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/4014372" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 4014372</span></a>]</div></dd><dt>116.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.116">Fisher SK, Erickson PA, Lewis GP, Anderson DH. Intraretinal proliferation induced by retinal
detachment. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1991;<span class="ref-vol">32</span>:1739–1748.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2032796" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 2032796</span></a>]</div></dd><dt>117.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.117">Geller SF, Lewis GP, Anderson DH, Fisher SK. Use of the MIB-1 antibody for detecting proliferating cells in
the retina. <span><span class="ref-journal">Invest Ophthalmol Vis Sci. </span>1995;<span class="ref-vol">36</span>:737–744.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7890504" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 7890504</span></a>]</div></dd><dt>118.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.118">Aramant RB, Seiler MJ. Progress in retinal sheet transplantation. <span><span class="ref-journal">Prog Retin Eye Res. </span>2004;<span class="ref-vol">23</span>:475–494.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15302347" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15302347</span></a>]</div></dd><dt>119.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.119">Fischer AJ, Reh TA. Muller glia are a potential source of neural regeneration in the
postnatal chicken retina. <span><span class="ref-journal">Nat Neurosci. </span>2001;<span class="ref-vol">4</span>:247–252.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11224540" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11224540</span></a>]</div></dd><dt>120.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.120">Fischer AJ, Reh TA. Potential of Muller cells to become neurogenic regeneration
retinal progenitor cells. <span><span class="ref-journal">Glia. </span>2003;<span class="ref-vol">43</span>:70–76.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12761869" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12761869</span></a>]</div></dd><dt>121.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.121">Tropepe V, Coles BL, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, van der Kooy D. Retinal stem cells in the adult mammalian eye. <span><span class="ref-journal">Science. </span>2000;<span class="ref-vol">287</span>:2032–2036.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10720333" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10720333</span></a>]</div></dd><dt>122.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.122">Kerns JM, Hinsman EJ. Neuroglial response to sciatic neurectomy. II. Electron
microscopy. <span><span class="ref-journal">J Comp Neurol. </span>1973;<span class="ref-vol">151</span>:255–280.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/4744474" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 4744474</span></a>]</div></dd><dt>123.</dt><dd><div class="bk_ref" id="ch37fisher.EXTYLES.123">Fisher SK, Anderson DH. Cellular effects of
detachment on the neural retina and the retinal pigment epithelium. In: Ryan SJ,
Wilkinson CP, editors. Retina, Surgical retina. Vol. 3. 3rd ed. St. Louis (MO):
Mosby; 2001.</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a>: © 2025 Webvision .<p class="small">All copyright for chapters belongs to the individual authors who created them. However, for non-commercial, academic purposes, images and content from the chapters portion of Webvision may be used with a non-exclusive rights under a Attribution, <a href="https://creativecommons.org/licenses/by-nc/4.0/" ref="pagearea=meta&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Noncommercial 4.0 International (CC BY-NC) Creative Commons license</a>. Cite Webvision, http://webvision.med.utah.edu/ as the source. Commercial applications need to obtain license permission from the administrator of Webvision and are generally declined unless the copyright owner can/wants to donate or license material. Use online should be accompanied by a link back to the original source of the material. All imagery or content associated with blog posts belong to the authors of said posts, except where otherwise noted.</p></div><div class="small"><span class="label">Bookshelf ID: NBK11552</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/21413405" title="PubMed record of this page" ref="pagearea=meta&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">21413405</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/webvision/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/webvision/retinal_degeneration/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/webvision/ch38macular/" title="Next page in this title">Next &gt;</a></div></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK11552/?report=reader">PubReader</a></li><li><a href="/books/NBK11552/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK11552" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK11552" style="display:none" title="Cite this Page"><div class="bk_tt">Fisher SK, Lewis GP, Linberg KA, et al. Cellular Remodeling in Mammalian Retina Induced by Retinal Detachment. 2005 May 1 [Updated 2007 Jul 3]. In: Kolb H, Fernandez E, Jones B, et al., editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK11552/pdf/Bookshelf_NBK11552.pdf">PDF version of this page</a> (5.8M)</li><li><a href="/books/n/webvision/pdf/">PDF version of this title</a> (235M)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ch37fisher.Introduction" ref="log$=inpage&amp;link_id=inpage">Introduction</a></li><li><a href="#ch37fisher.Levels_of_Remodeling" ref="log$=inpage&amp;link_id=inpage">Levels of Remodeling</a></li><li><a href="#ch37fisher.The_Details_of_Cellu" ref="log$=inpage&amp;link_id=inpage">The Details of Cellular Remodeling after Detachment and Reattachment</a></li><li><a href="#ch37fisher.Protein_Expression_i" ref="log$=inpage&amp;link_id=inpage">Protein Expression in Cone Photoreceptors after Detachment: Analyzing the
Surviving Cone Photoreceptor Array</a></li><li><a href="#ch37fisher.Remodeling_of_Photor" ref="log$=inpage&amp;link_id=inpage">Remodeling of Photoreceptors after Reattachment</a></li><li><a href="#ch37fisher.Remodeling_of_Second" ref="log$=inpage&amp;link_id=inpage">Remodeling of Second- and Third-Order Neurons</a></li><li><a href="#ch37fisher._Remodeling_of_Gangli" ref="log$=inpage&amp;link_id=inpage">Remodeling of Ganglion Cells</a></li><li><a href="#ch37fisher.Glial_Cell_Remodelin" ref="log$=inpage&amp;link_id=inpage">Glial Cell Remodeling</a></li><li><a href="#ch37fisher.Retinal_Remodeling_a" ref="log$=inpage&amp;link_id=inpage">Retinal Remodeling after Detachment and Reattachment: An Overview</a></li><li><a href="#ch37fisher.Future_Challenges" ref="log$=inpage&amp;link_id=inpage">Future Challenges</a></li><li><a href="#ch37fisher.AFN1" ref="log$=inpage&amp;link_id=inpage">About the Author</a></li><li><a href="#ch37fisher.References" 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