Axonal Sprouting of GABAergic Neurons in Epileptogenesis

癫痫的发生，即正常大脑变得长期容易癫痫发作的过程，人们知之甚少。许多中枢神经系统损伤(如中风、创伤、神经退行性疾病)可以诱发癫痫发生，但目前还没有治疗方法来阻止这一过程。虽然脑生理学中的神经元重组和改变与癫痫发生有关，但这些改变对癫痫发生的功能后果和相对重要性，以及这些改变对癫痫发生和发作发生的功能后果和相对重要性尚不清楚。神经元重组和生理改变背后的许多分子、细胞和遗传机制也同样未知。这一信息对于为旨在干扰癫痫发生的新疗法的开发提供合理的基础至关重要。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萌发，2)颗粒细胞-GABA能神经元间突触的发生率增加，但单个苔藓纤维突触对间神经元的输入更弱或更不可靠，3)不同的神经元群体表达与突触重排相关的轴突引导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测试这些假说。将结合使用解剖学、电生理学、分子生物学和遗传学方法。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变化，鉴定和生理特征新的异常兴奋性输入到癫痫齿状回中的GABA能中间神经元，并定义编码调节与癫痫相关的突触重组的关键指导线索的遗传程序。这项研究的结果将有助于更详细地了解参与癫痫、记忆和海马区信息处理的突触电路的调节，并为在慢性癫痫发作之前阻止癫痫发生的新疗法的开发提供洞察力。

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.