Epigenetic Mechanisms in Epilepsy-Related Memory Formation

 描述(由申请人提供)：人们正在形成共识，认为几种癫痫疾病，包括人类癫痫的一种部分成人发作形式--颞叶癫痫(TLE)，往往与严重的长期认知障碍有关。目前，还没有有效的治疗方法来预防或逆转癫痫相关的记忆丧失，其潜在的分子机制仍然难以捉摸。我们实验室和其他实验室最近的工作表明，癫痫患者存在表观遗传学DNA甲基化(DNAME)调节异常。因此，我们认为DNAME可能是癫痫海马区异常基因转录的主要贡献者。由于先前的研究表明，脑源性神经营养因子(BDNF)基因的表达是记忆形成所必需的，并且在癫痫患者和自发癫痫大鼠的海马区都存在显著的失调，因此我们将重点研究TLE患者记忆形成过程中脑源性神经营养因子在海马区兴奋性突触中的表观遗传调节。有趣的是，表观遗传学在调节行为诱导的癫痫海马区BDNF基因表达变化中的作用在很大程度上还没有定论。我们将在我们的TLE实验模型中使用DNMT抑制剂和蛋氨酸来操作DNAME，以深入了解治疗癫痫相关记忆丧失的潜在治疗靶点。由于这些抑制剂已经在临床上使用，或正在肿瘤学中积极研究和开发，因此有可能迅速转化为治疗癫痫相关的记忆障碍以及人类的其他共病，如抑郁和焦虑。这一建议的中心假设是，癫痫海马区异常的DNAME介导的记忆允许基因的转录调控，如BDNF，有助于癫痫相关的记忆损伤。采用新的方法和技术手段，本建议的目的如下：1)测试DNAME对CA1区锥体神经元BDNF基因的调控是否在TLE实验性啮齿动物模型的记忆形成过程中发生改变；2)测试蛋氨酸治疗是否逆转TLE的两种癫痫表型、海马网多动和海马依赖记忆形成。在细胞和分子水平上了解与TLE相关的记忆障碍的病理生理机制，并评估潜在的治疗策略，无疑是与这种神经疾病相关的认知障碍研究的首要任务。

 DESCRIPTION (provided by applicant): A consensus is building that several epilepsy disorders, including Temporal lobe epilepsy (TLE), a partial adult onset form of human epilepsy, are often associated with significant long-term cognitive impairments. Currently, no effective treatment options exist to prevent or reverse epilepsy-related memory loss, and the underlying molecular mechanisms remain elusive. Recent work from our lab and others has implicated abnormal epigenetic DNA methylation (DNAme) regulation in epilepsy. Thus, we propose that DNAme may be a major contributor of aberrant gene transcription in the epileptic hippocampus. Because, previous studies have demonstrated that brain derived neurotrophic factor (Bdnf) gene expression is required for memory formation and is significantly dysregulated in the hippocampi of both epileptic patients and spontaneously seizing rats, we will focus our studies by investigating epigenetic regulation of Bdnf at excitatory synapses in the hippocampus during memory formation with TLE. Intriguingly, the role of epigenetics in mediating behaviorally- induced Bdnf gene expression changes in the epileptic hippocampus is largely uncharacterized. We will manipulate DNAme with DNMT inhibitors and Methionine in our experimental model of TLE, to gain insights into potential therapeutic targets for the treatment of epilepsy-related memory loss. Since these inhibitors are already in use clinically or being aggressively studied and developed in oncology, there is the potential to rapidly translate to treatments for epilepsy-related memory impairments and other comorbidities such as depression and anxiety in humans. The central hypothesis of this proposal is that aberrant DNAme mediated transcriptional regulation of memory permissive genes, like Bdnf, in the epileptic hippocampus contributes to epilepsy-related memory impairments. Using novel methodical and technical approaches, the aims of this proposal are as follows: 1) to test whether Bdnf gene regulation by DNAme is altered in CA1 pyramidal neurons during memory formation in an experimental rodent model of TLE, and 2) to test whether treatment with methionine reverses two-epileptic phenotypes, hippocampal network hyperactivity and hippocampus-dependent memory formation in TLE. Understanding the pathophysiological mechanisms of memory deficits associated with TLE at the cellular and molecular levels and evaluation of potential therapeutic strategies undoubtedly take priority in the path of research on cognitive impairments associated with this neurological disorder.