Axonal Sprouting of GABAergic Neurons in Epileptogenesis

癫痫发生，即正常大脑变得长期倾向于癫痫发作的过程，人们知之甚少。许多CNS损伤（即中风、创伤、神经退行性疾病）可诱导癫痫发生，但目前还没有治疗方法来阻止这一过程。虽然神经元重组和脑生理学改变与癫痫发生有关，但这些变化对癫痫发生的功能后果和相对重要性，这些变化对癫痫发生和癫痫发作发生的功能后果和相对重要性仍然未知。许多神经元重组和生理改变的分子、细胞和遗传机制同样是未知的。这一信息是至关重要的，在提供一个合理的基础上，旨在破坏癫痫发生的新疗法的发展。我们的假设是在癫痫发生过程中1）GABA能神经元经历癫痫发作诱导的轴突发芽，2）相互颗粒细胞-GABA能中间神经元突触的发生率增加，但个体苔藓纤维突触输入到中间神经元上较弱或较不可靠，3）不同的神经元群体表达与突触重排相关的轴突导向分子的独特基因表达模式。我们将使用两种不同的颞叶癫痫模型在癫痫发生过程中的多个时间点检验这些假设。将使用解剖学、电生理学、分子生物学和遗传学方法的组合。这些实验的结果将记录癫痫发生过程中GABA能中间神经元的形态学变化，识别和生理学表征癫痫齿状回GABA能中间神经元的异常兴奋性输入，并定义编码调节癫痫相关突触重组的关键指导线索的遗传程序。拟议的研究结果将有助于更详细地了解海马中癫痫，记忆和信息处理所涉及的突触电路的调节，并为开发新的治疗方法以在慢性癫痫发作发展之前阻止癫痫发生提供见解。

Epileptogenesis, the process by which a normal brain become chronically prone to seizures, is poorly understood. Many CNS insults (i.e. stroke, trauma, neurodegenerative disease) can induce epileptogenesis, yet no therapies currently exist to arrest this process. Although neuronal reorganization and alterations in brain physiology are associated with epileptogenesis, the functional consequences and relative importance of these changes to epileptogenesis, the functional consequences and relative importance of these changes to epileptogenesis and seizure genesis remain unknown. Many of the molecular, cellular and genetic mechanisms underlying neuronal reorganization and physiological alterations are likewise unknown. This information is crucial in providing a rational basis for the development of new therapies designed to disrupt epileptogenesis. Our hypothesis are that during epileptogenesis 1) GABAergic neurons undergo seizure- induced axonal sprouting, 2) the incidence of reciprocal granule cell- GABAergic interneuron synapses is increased, but individual mossy fiber synaptic inputs onto interneurons are weaker or less reliable and 3) different neuronal populations express unique gene expression patterns for axon guidance molecules associated with synaptic rearrangements. We will test these hypothesis at multiple time points during epileptogenesis using two different models of temporal lobe epilepsy. A combination of anatomical, electrophysiological, molecular biological and genetic approaches will be used. Results from these experiments will document morphological changes in GABAergic interneurons during epileptogenesis, identify and physiologically characterize novel aberrant excitatory inputs onto GABAergic interneurons in the epileptic dentate gyrus, and define genetic programs that encode the critical guidance cues regulating the synaptic reorganization associated with epilepsy. Results from the proposed study will contribute to a more detailed understanding of the regulation of the synaptic circuitry involved in epilepsy, memory and information processing in the hippocampus and provide insight for development of novel therapies to arrest epileptogenesis before chronic seizures develop.