Activity-Dependent Gene Expression in Epileptogenesis

描述(由申请人提供)： 癫痫是一种常见的神经疾病，由自发性脑兴奋引起，影响高达1.0%的人口。它会导致无法控制的正常功能丧失，并可迅速扩散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涉及调节神经元兴奋性的基因突变，但大多数患者并没有这种突变，而是有引发癫痫发作的大脑局部区域。究竟是什么使人类新皮质癫痫的这些区域仍然难以捉摸，也不清楚正在进行的癫痫样活动在加强这种状态方面发挥了什么作用。可能是活性依赖的信号通路调节基因表达的变化，从而导致神经元连接性和兴奋性的变化。我们最近发现，在癫痫发作的起始区，诱导EGR和AP1转录因子的通路被激活。这些通路可能通过改变突触的效力和可塑性来促进癫痫状态。我们假设癫痫扩散区域代表“早期”癫痫发生区域，并且有不同于代表“晚期”癫痫发生的癫痫发作区域的基因表达变化。在这项建议中，我们将使用硬膜下记录电极来定位药物难治性癫痫患者的新皮质癫痫灶，并使用寡核苷酸微阵列测量这些灶和癫痫早期扩散区域的差异基因表达。关键可塑性相关基因的表达水平将得到确认，并确定其细胞定位。了解活动依赖的基因表达和所涉及的细胞类型将为人类癫痫的发生提供新的见解，有助于临床治疗，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.