Genetic Regulation of Seizure-Induced Neurogenesis

描述(由申请人提供)：这项建议的目标是确定兴奋性毒性细胞死亡脆弱或抗性近交系小鼠品系的等位基因变异是否调节基础和癫痫诱导的成人前脑神经发生。最近的研究表明，成人持续性神经发生的异常调节导致了海马区的过度兴奋性和与颞叶癫痫相关的认知问题。尽管持续性前脑神经干细胞及其在脑修复治疗中的潜在作用引起了人们的浓厚兴趣，但对完整和受损大脑中神经发生的调控知之甚少。我们(J.Parent博士)和其他人最近发现，实验性癫痫发作增加了成年啮齿动物前脑中的神经发生，并诱导了异位神经母细胞迁移。这些效应背后的分子机制尚不清楚。我们(P.Schauwecker博士)还发现，某些近交系小鼠在红藻氨酸(KA)诱导的癫痫持续状态(SE)后，细胞死亡的程度明显不同。通过结合两种跨学科的方法来解决癫痫发生中网络功能的改变，我们计划调查遗传变异和细胞死亡对成人神经发生的影响。这项合作提案是对青少年研究人员癫痫研究探索性奖项项目公告的回应，将检验两个假设：(1)成年小鼠齿状回和室下区(SVZ)的神经发生受到等位基因变异的影响；(2)组织损伤是刺激成年小鼠前脑中神经发生和异位神经母细胞迁移所必需的。具体目的是：1)确定癫痫耐受(C57BL/6)或易感(FVB/N)小鼠的基础成年海马神经元发生的差异；2)确定SVZ嗅球神经发生在成年C57BL/6和FVB/N小鼠中是否受到差异调控；3)使用我们的基因定义的小鼠品系的模型来确定癫痫诱导的齿状回神经发生是否由损伤触发；以及4)确定KA诱导的细胞死亡敏感或抵抗小鼠之间是否存在SVZ神经发生或异位神经母细胞迁移的不同。这项合作的结果将为癫痫的新型干细胞疗法提供进一步的洞察力，并有助于确定这种神经疾病的有效预防策略和合理的治疗设计。

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.