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Review
. 2014 Mar 14:7:18.
doi: 10.3389/fnmol.2014.00018. eCollection 2014.

Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation

Candi L Lasarge  1 , Steve C Danzer  2
Affiliations
Review

Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation

Candi L Lasarge et al. Front Mol Neurosci. .

Abstract

The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.

Keywords: PTEN; TSC; autism; epilepsy; granule cells; hippocampus; mTOR; neurogenesis.

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Figures

FIGURE 1
FIGURE 1
PI3K/PTEN–mTOR pathway. mTOR is activated by signaling through the PI3K–Akt pathway, regulating cell growth and proliferation. PTEN, TSC1, and TSC2 act as negative regulators of the mTOR pathway, and removal leads to hyperactivation of mTOR. mTOR complex 1 (mTORC1) signaling requires activation of the adaptor protein raptor, and mTOR complex 2 (mTORC2), which is largely insensitive to acute rapamycin treatment, requires activation of the rictor protein. Although regulation of mTORC2 is less clearly defined, it has been linked to cytoskeleton organization.
FIGURE 2
FIGURE 2
Dentate granule cells lacking PTEN have hyperactive mTOR signaling. Confocal maximum projections of the dentate gyrus from control mice, Gli1-CreERT2 × PTENfl/fl (PTEN KO) mice, and rapamycin treated PTEN KO mice immunostained for phosphorylated ribosomal protein S6 (pS6; red). pS6, the downstream target of mTOR complex 1, is greatly increased in the dentate granule cell layer (DGC-L) in the PTEN KO animal, demonstrating the upregulation of mTOR signaling with the removal of PTEN. Rapamycin treatment, and thus inhibition of mTOR, prevents the increase in pS6 in PTEN KO mice. Scale bar = 25 μm. Images courtesy of Isaiah Rolle.
FIGURE 3
FIGURE 3
Dentate granule cells lacking PTEN exhibit structural abnormalities. Confocal maximum projections of control and Gli1-CreERT2 × PTENfl/fl (PTEN KO) granule cells, filled with biotin and labeled with Alexa-Fluor 594-conjugated streptavidin. The PTEN KO cell exhibits somatic hypertrophy and dramatically increased dendritic thickness compared to the control dentate granule cell. Additionally, basal dendrites are commonly found on the PTEN-negative cells, here indicated by blue arrows. White arrowheads highlight the mossy fiber axon extending toward the hilus from each of the two cells. Scale bar = 50 μm. Images courtesy of Victor R. Santos and Dr. Raymund Y. K. Pun.
FIGURE 4
FIGURE 4
Tuberous sclerosis complex deficiency induces multiple axons in culture. Knockdown of Tsc2 by shRNA (shTsc2) or knockout of Tsc1 (Cre) induced multiple axons in vitro. (A) E18 rat hippocampal neurons transfected with either enhanced green fluorescent protein (EGFP) alone or EGFP together with Tsc2 shRNA. Tsc2 knockdown induced multiple axons, all of which are positive for Tau1. (B) E17 mouse hippocampal neurons from Tsc1lox/flox embryos transfected with EGFP alone or EGFP together with Cre. Arrowheads indicate axons positive for Tau1. Scale bars = 20 μm. Reprinted with permission from Choi et al. (2008).
FIGURE 5
FIGURE 5
Mossy fiber sprouting is present in mice with PTEN removal from dentate granule cells. Confocal maximum projections of hippocampi from tamoxifen-treated control and Gli1-CreERT2 × PTENfl/fl (PTEN KO) mice immunostained for GFP (red) and zinc-transporter 3 ZnT3 (cyan) are shown. ZnT3-labeling reveals the normal dentate granule cell mossy fiber axon terminal field (hilus and stratum lucidum) in the control animal, while mossy fiber sprouting into the dentate granule cell layer (DGC-L) and inner molecular layer (IML) is evident in the knockout animal (green boxes in the top row correspond to high resolution images shown in the bottom row). Scale bars = 200 μm (top row) and 30 μm (bottom row). Reprinted with permission from Pun et al. (2012).
FIGURE 6
FIGURE 6
Cell-intrinsic effects of altered mTOR signaling and network influence. In addition to cell-intrinsic effects from disrupted mTOR signaling in cells lacking PTEN, TSC1, or TSC2 (red “KO” cells), these cells may respond inappropriately to surrounding wild type (WT) cells and/or cause WT cells to behave abnormally. These altered dynamics may produce an abnormal network, facilitating epileptogenesis.
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