Genetic Regulation of Seizure-Induced Neurogenesis

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DESCRIPTION (provided by applicant): The goal of this proposal is to determine whether allelic variation of excitotoxic cell death-vulnerable or -resistant inbred mouse strains modulates basal and seizure-induced adult forebrain neurogenesis. Recent studies suggest that aberrant regulation of persistent neurogenesis in the adult contributes to hippocampal hyperexcitability and cognitive problems associated with temporal lobe epilepsy. Despite the intense interest in persistent forebrain neural stem cells and their potential utility for brain repair therapies, little is known about the regulation of neurogenesis in the intact and injured brain. We (Dr. J. Parent) and others recently have found that experimental seizures increase neurogenesis and induce ectopic neuroblast migration in the adult rodent forebrain. The molecular mechanisms underlying these effects remain unknown. We (Dr. P. Schauwecker) have also discovered that certain inbred strains of mice differ markedly in the extent of cell death after kainic acid (KA)-induced status epilepticus (SE). By combining two cross disciplinary approaches to address altered network function in epileptogenesis, we plan to investigate the influence of genetic variation and cell death on adult neurogenesis. This collaborative proposal, a response to the program announcement for Exploratory awards in Epilepsy Research for Junior Investigators, will test two hypotheses: (1) Adult murine dentate gyrus and subventricular zone (SVZ) neurogenesis are influenced by allelic variation; and (2) Tissue injury is required to stimulate neurogenesis and ectopic neuroblast migration in the adult mouse forebrain. The specific aims are: 1) To determine whether basal adult hippocampal neurogenesis varies in mice resistant (C57BL/6) or susceptible (FVB/N) to seizure-induced cell death; 2) To establish whether SVZ-olfactory bulb neurogenesis is differentially regulated in adult C57BL/6 and FVB/N mice; 3) To determine whether seizure-induced dentate gyrus neurogenesis is triggered by injury using our model of genetically-defined murine strains; and 4) To determine whether seizure-induced SVZ neurogenesis or ectopic neuroblast migration differs between KA-induced cell death susceptible or resistant mice. The results of this collaboration will provide further insight into novel stem cell treatments for epilepsy and aid in determining effective preventative strategies and rational therapeutic designs for this neurological disorder.