Role of CACHD1 in the development of temporal lobe epilepsy and absence epilepsy

癫痫是美国公众的主要经济和个人负担，影响超过300万人 美国人（占人口的1-2%），每年诊断出超过20万例新病例。无法治愈 癫痫癫痫发作只能用抗癫痫药物来抑制。不幸的是，这些药物是无效的 在大约30%的患者中，并且通常与不良副作用有关。 T-型钙通道（T-channels）在控制神经元兴奋性中起重要作用。T- 通道在许多神经元的静息膜电位附近打开，使它们能够充当起搏器 触发钠依赖性动作电位的电流。T通道表达和活性的增加 在颞叶癫痫（TLE）的动物模型中有报道，导致神经元过度兴奋。在 失神性癫痫，T通道活动与丘脑皮质网络振荡有关， 棘波放电（SWD）。尽管越来越多的证据表明T通道在TLE和缺失中的作用， 在癫痫中，T通道活性和表达水平增加的机制知之甚少， 促进神经元兴奋性和癫痫易感性的增加。我们最近发现了一种新的T型通道 调节剂，Ca 2+通道和趋化性受体结构域1（CACHD 1）蛋白。CACHD 1是 结构上类似于gabapentinoids的主要靶点β 2 β亚基。CACHD 1在两种组织中都有高表达， 人类和啮齿类动物海马和丘脑脑区与所有三个T- 通道子类型。CACHD 1促进T通道的细胞表面表达水平并增加峰值电流 密度，导致神经元兴奋性增加和癫痫易感性增加。敲除 CACHD 1预防γ-丁内酯（GBL）诱导的失神发作并延迟点燃发作 并减少癫痫发作的持续时间。鉴于这些发现，CACHD 1可以促进神经元的增加， 与TLE和失神癫痫相关的兴奋性，使其成为治疗的新靶点。在本提案中，我们 将检验我们的中心假设，即CACHD 1通过增加T通道增加神经元兴奋性 功能，促进失神癫痫和TLE的发作和严重程度。在完成这些 这些研究将推进我们目前对CACHD 1在缺失发展中的作用的理解。 癫痫和TLE，为治疗开发提供了新的靶点。

Epilepsy is a major economic and personal burden for the American public, affecting over 3 million Americans (1-2% of the population) with over 200,000 new cases diagnosed each year. There is no cure for epilepsy. Seizures can only be suppressed using antiepileptic drugs. Unfortunately, these drugs are ineffective in approximately 30% of patients and are often associated with adverse side effects. T-type calcium channels (T-channels) play an important role in controlling neuronal excitability. T- channels open near the resting membrane potential of many neurons, allowing them to act as pacemaker currents that trigger sodium dependent action potential. Increases in T-channel expression and activity have been reported in animal models of temporal lobe epilepsy (TLE), contributing to neuronal hyperexcitability. In absence epilepsy, T-channel activity has been linked to thalamocortical network oscillations that give rise to spike wave discharges (SWD). Despite growing evidence for a role of T-channels in both TLE and absence epilepsy, little is known about the mechanisms by which T-channel activity and expression levels are increased, facilitating increases in neuronal excitability and seizure susceptibility. We recently discovered a novel T-channel modulator, the Ca2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is structurally similar to 2 subunits, the major target of gabapentinoids. CACHD1 is highly expressed in both human and rodent hippocampal and thalamic brain regions with overlapping expression patterns to all three T- channel subtypes. CACHD1 promotes cell surface expression levels of T-channels and increases peak current densities, leading to an increase in neuronal excitability and increased seizure susceptibility. Knockout of CACHD1 prevents γ-butyrolactone (GBL) induced absence seizures and delays the onset of kindled seizures and reduces seizure durations. In view of these findings, CACHD1 could facilitate increases in neuronal excitability associated with TLE and absence epilepsy, making it a novel target for therapy. In this proposal we will test our central hypothesis that CACHD1 increases neuronal excitability via increases in T-channel function, facilitating the onset and severity of both absence epilepsy and TLE. On completion of these studies we will have advanced our current understanding for the role of CACHD1 in the development of absence epilepsy and TLE, providing a novel target for therapy development.