Activity-Dependent Gene Expression in Epileptogenesis

描述（由申请人提供）： 癫痫是一种常见的自发性脑兴奋的神经系统疾病，影响高达1.0%的人口。它导致无法控制的正常功能丧失，可以迅速蔓延并演变为全身性惊厥。虽然在一小部分遗传性癫痫患者中发现了参与调节神经元兴奋性的基因突变，但大多数患者不具有此类突变，而是具有引发癫痫发作的局灶性脑区域。究竟是什么使人类新皮层的这些区域癫痫仍然是难以捉摸的，也不清楚持续的癫痫样活动在增强这种状态中起着什么作用。可能的是，活性依赖性信号传导途径调节基因表达变化，从而导致神经元连接性和兴奋性的变化。我们最近发现，激活的途径诱导EGR和AP1转录因子在癫痫发作的区域。这些通路可以通过改变突触效能和可塑性来促进癫痫状态。我们假设，癫痫发作蔓延的地区代表地区的“早期”癫痫和基因表达的变化，从癫痫发作的地区，代表“晚期”癫痫。在这个建议中，我们将使用硬膜下记录电极映射人类新皮层癫痫灶患者的药物难治性癫痫发作，并测量差异基因表达在这些病灶和在该地区的早期癫痫发作蔓延使用寡核苷酸微阵列。将确认关键可塑性相关基因的表达水平，并确定其细胞定位。了解活性依赖性基因表达和所涉及的细胞类型将为人类癫痫发生提供新的见解，这将有助于临床管理，并为癫痫患者提供新的治疗途径。

DESCRIPTION (provided by applicant): Epilepsy is a common neurological disorder of spontaneous brain excitation that effects up to 1.0% of the population. It results in uncontrolled loss of normal function that can spread rapidly and evolve into a generalized convulsion. While mutations in genes involved in modulating neuronal excitability have been identified for a small proportion of patients with inherited epilepsy, the majority of patients do not possess such mutations, but instead have focal brain regions that initiate seizures. Exactly what makes such areas of human neocortex epileptic remains elusive, and it is also unclear what role ongoing epileptiform activity plays in potentiating this state. It is likely that activity dependent signaling pathways regulate gene expression changes which lead to changes in neuronal connectivity and excitability. We have recently shown the activation of pathways inducing EGR and AP1 transcription factors at regions of seizure onset. These pathways could promote the epileptic state through alterations in synaptic efficacy and plasticity. We hypothesize that regions of seizure spread represent regions of "early" epileptogenesis and have gene expression changes distinct from regions of seizure onset which represent "late" epileptogenesis. In this proposal, we will use subdural recording electrodes to map human neocortical epileptic foci in patients with medically intractable seizures, and measure differential gene expression at these foci and at regions of early seizure spread using oligonucleotide microarrays. The expression level of key plasticity-associated genes will be confirmed and their cellular localization determined. Understanding activity-dependent gene expression and the cell types involved will provide new insights into human epileptogenesis that will aid in clinical management and offer new therapeutic avenues for patients with epilepsy.