Activity-Dependent Gene Expression in Human Epilepsy

我们已经开发了功能基因组学方法来鉴定人类局灶性癫痫区域新皮层的差异表达基因。我们发现，不管癫痫的病因是什么，所有患者都有一小群基因被诱导。这些持续诱导的基因大多属于一个已被充分研究的用于学习和记忆的途径，包括MAP激酶信号，即时早期基因/转录，以及突触的发育和加强。由于这些基因的表达与间歇放电频率密切相关，因此它们是癫痫新皮层极其可靠的标记。作为了解它们在癫痫中的作用的一种手段，我们已经将这些基因中的一些映射到6层人类癫痫新皮层中的特定神经元上。在这些癫痫区，我们发现持续诱导磷酸creb和相应的突触脊柱密度增加。这些发现产生了一个有趣的假设，即持续的癫痫活动产生持续的MAPK信号和基因激活，促进结构和功能变化，以维持慢性癫痫状态。本研究的第一个目的是将MAPK通路中的信号中间体与人类癫痫新皮层中活性依赖基因的诱导和突触组织的变化联系起来。二是利用大鼠癫痫模型来确定MAPK信号在基因表达、突触变化和癫痫活动中的功能重要性，以便我们能够开发新的人类抗癫痫治疗方法。

We have developed functional genomic methods to identify differentially expressed genes within focal epileptic regions of human neocortex. We discovered the induction of a small group of genes in all patients, regardless of the cause of their epilepsy. Most of these persistently-induced genes belong to a well-studied pathway used in learning and memory that includes MAP kinase signaling, immediate-early gene/transcription, and synaptic development and strengthening. These genes are extremely reliable markers of epileptic neocortex as their expression correlates precisely with interictal discharge frequency. As a means to understand their role in epilepsy, we have mapped some of these genes to specific neurons within the 6-layered human epileptic neocortex. Within these epileptic regions, we found a persistent induction of phospho-CREB and a corresponding increase in synaptic spine density. These findings generate an intriguing hypothesis that ongoing epileptic activity produces sustained MAPK signaling and gene activations that promote structural and functional changes to maintain the chronic epileptic state. The first aim in this proposal is to relate signaling intermediates in the MAPK pathway to activity-dependent gene induction and changes in synaptic organization in human epileptic neocortex. The second is to use an epileptic model in the rat to determine the functional importance of MAPK signaling on gene expression, synaptic changes, and epileptic activities so that we can develop novel human antiepileptic therapeutics.