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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS048064-03
Application #
7236005
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fureman, Brandy E
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$170,035
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Hamberger, Marla J; Seidel, William T; McKhann 2nd, Guy M et al. (2010) Game-changing, or business as usual? New findings on naming skills after temporal lobe surgery. Neurology 75:1572