Adult Subventricular Zone Gliogenesis in Limbic Epilepsy

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DESCRIPTION (provided by applicant): Human temporal lobe epilepsy (TLE) varies in the degree of neuronal loss and synaptic reorganization, but is always characterized by hippocampal "reactive" gliosis. Astrogliosis has long been associated with focal epilepsy, yet studies to date have failed to establish how glial cells may influence seizures in TLE. Hippocampal astrocytes recorded from epileptic rats treated with the convulsant pilocarpine and from resected epileptic human temporal lobe have electrophysiological features of immature astrocytes. This proposal will test the hypothesis that seizures induce abnormal gliogenesis and the ultimate consequence is that the risk of subsequent seizures increases. Hippocampal glial cells generated in response to seizures could theoretically arise from migration and differentiation of sub-ventricular zone (SVZ) or sub-granular zone (SGZ) progenitor cells, from local endogenous precursor cells or from re-entry into the cell cycle of mature astrocytes. Building on the applicant's previous investigation of glial cell properties in the control and epileptic hippocampus, this proposal will use a combination of retroviral mediated gene transfer, electrophysiological and immunohistochemical techniques to investigate seizure induced SVZ and SGZ gliogenesis. We will compare the time course, cell fate and physiological consequences of SVZ and SGZ derived hippocampal gliogenesis in the rat pilocarpine limbic epilepsy model. In addition, we will determine the consequences of focally ablating the SVZ and/or hippocampus progenitor pool prior to the induction of seizures. Specific Aim 1: To determine whether seizures induce migration of progenitor cells to and subsequent gliogenic differentiation within the hippocampus. Specific Aim 2: To determine whether the glial cells that are generated in response to seizures remain immature, by electrophysiological and molecular criteria. Specific Aim 3: To determine whether selective disruption of cellular proliferation in the SVZ and the hippocampus influences glial development and epileptogenesis.