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. 2002 Jun 1;22(11):4286-92.
doi: 10.1523/JNEUROSCI.22-11-04286.2002.

Vascular defects and sensorineural deafness in a mouse model of Norrie disease

Heidi L Rehm  1 , Duan-Sun Zhang, M Christian Brown, Barbara Burgess, Chris Halpin, Wolfgang Berger, Cynthia C Morton, David P Corey, Zheng-Yi Chen
Affiliations

Vascular defects and sensorineural deafness in a mouse model of Norrie disease

Heidi L Rehm et al. J Neurosci. .

Abstract

Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.

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Figures

Fig. 1.
Fig. 1.
Audiology aligned with histopathological analysis.A, ABRs to pure tone bursts in knock-out (red) and control (blue) mice, separated into three age groups. Thresholds are plotted with highest sensitivity (lowest SPL) upward on the graphs for comparison with the human audiogram shown in Figure 2. Arrows indicate no response to the highest sound pressure level tested (85 dB SPL).B, Difference in average threshold shifts compared with a 3–4 month control average. Asterisks indicate statistically significant differences at the indicated frequency.C–F, Pathology in indicated regions of the cochlea in knock-out (red) and control (blue) mice, separated into three age groups. The system for rating pathology in the inner and outer hair cells and the spiral ganglion was based on the quantity of hair cells or neurons lost. The system for rating pathology in the stria vascularis was based on the presence of the various types of pathology described in Figure 4. Ratings for each mouse in each region were averaged to get an overall rating for the group. Bars indicate 1 SD. The significance of separating the pathology into three regions is attributable to the tonotopic organization of the cochlea, with low frequencies detected in the apex (A) of the cochlea, middle frequencies in the middle (M), and high frequencies in the base (B). This allows comparison of the audiological data with the histopathology.
Fig. 2.
Fig. 2.
Audiogram of a 40-year-old patient with Norrie disease. Symbols (×, left ear; ○, right ear) represent threshold response levels for the tones at the indicated frequencies relative to normal. There is a severe bilateral sensorineural hearing loss with elevated threshold (lower sensitivity) for sounds at all frequencies. The arrow indicates no response at the highest sound level tested.
Fig. 3.
Fig. 3.
Histology of knock-out and control mouse cochleas.A, A normal cochlea from the apical turn of a 3.2-month-old control mouse. The arrowhead indicates an inner hair cell; arrows indicate outer hair cells.B, Abnormal cochlea from the apical turn of a 3.2-month-old knock-out mouse. Note the enlarged vessels (arrowheads). C, Normal cochlea from the apical turn of a 15-month-old control mouse. D, Abnormal cochlea from the apical turn of a 15-month-old knock-out mouse. Note the degenerated stria vascularis (filled arrowhead), degenerated spiral ganglion (open arrowhead), and loss of outer hair cells (arrow). oc, Organ of Corti;rm, Reissner's membrane; sg, spiral ganglion; sl, spiral ligament; sv, stria vascularis; tm, tectorial membrane. Scale bar, 100 μm.
Fig. 4.
Fig. 4.
Histology of the stria vascularis.A, A normal stria vascularis from the basal turn of a 15-month-old control mouse. A normal distribution of nuclei from basal (b), intermediate (i), and marginal (m) cells is present. Normal basal infoldings (bi) extending from the marginal and intermediate cells and surrounding the capillaries (c) are seen. The adjacent spiral ligament (spl) is also shown. B, Stria from the apical turn of a 3.2-month-old knock-out mouse showing enlarged vessels (arrowheads indicate endothelial cell nuclei).C, Stria from the basal turn of a 3.2-month-old knock-out mouse showing excessive numbers of cells in the intermediate cell layer (asterisks indicate nuclei). The origin of these cells is not known. D, Stria from the middle region of the cochlea of a 6.5-month-old knock-out mouse showing cell loss and replacement by large intracellular spaces. E, Stria from the basal turn of a 15-month-old knock-out mouse showing a complete loss of marginal cells (top).F, Stria from the apical turn of a 15-month-old knock-out mouse showing severe degeneration of the whole structure. Scale bar, 10 μm.
Fig. 5.
Fig. 5.
Comparison of vessel size. The distribution of cross-sectional vessel diameters for control (black) and knock-out (gray) mice at 3–4 months is shown. Theinset shows the average number of vessels per turn in control (black) and knock-out (gray) mice, separated by age. Bars indicate 1 SD.
Fig. 6.
Fig. 6.
Fluorescent dye fills of cochlear vasculature.A, Portion of the apical turn of the stria vascularis in a 2-month-old control mouse. B, Apical turn of a 2-month-old knock-out mouse. Note the enlarged capillary on theleft and the thin and sparsely distributed vessels on the right. C, Basal turn of the stria vascularis in a 2-month-old control mouse. D, Basal turn of the stria vascularis in a 2-month-old knock-out mouse. Note the large vessel at the bottom. E, Top view of the apical turn of the cochlea in a 3.5-month-old control mouse.F, Similar view of the cochlea in a 3.5-month-out knock-out mouse. Note the large vessels in the stria vascularis (sv) and sparse distribution of vessels in the spiral ganglion (sg). G, Inner retina from a 13-month-old control mouse. H, Inner retina from a 13-month-old knock-out mouse. I, Outer retina from a 13-month-old knock-out mouse. J, Outer retina from a 13-month-old knock-out mouse. [The partial vasculature at thetop of the image is attributable to a fold from the inner retina (see top ofH).]
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