The role of CA2 in epilepsy and social comorbidity

项目摘要 颞叶癫痫(TLE)的一个关键挑战是确定导致癫痫发作的神经机制 癫痫发作是因为目前的药物不能治疗所有癫痫发作，而且通常伴随着使人虚弱的副作用。 此外，目前的药物不能治疗癫痫患者经常表现出的社会行为变化， 包括增加社会攻击性。这个项目将挑战目前关于病理生理学的教条。 海马体如何在TLE癫痫发作中起作用的基础，主要集中在TLE的三个主要区域 海马区：齿状回、CA3和CA1。相反，我们研究了CA2区域，这是一个相对较小的区域 海马体，很少受到关注，但已知在TLE患者和TLE患者中存活相对完整 啮齿动物模型，可作为癫痫发作的焦点或促进癫痫发作的传播。实验工具 在两个首席调查员的实验室中开发，现在可以直接调查 利用表达Cre重组酶的小鼠系研究CA2在小鼠TLE模型中的重要性 相对选择性地存在于CA2主神经元。依赖Cre的病毒载体将用于基因表达 CA2主神经元的编码工具用于检测TLE中CA2回路的变化和TLE的影响 在癫痫发作时CA2急性或慢性沉默。因此，我们将确定CA2是否控制药理作用 在健康大脑中诱发急性癫痫发作和/或在癫痫脑中诱发慢性癫痫发作。我们还将 确定CA2在报道的小鼠社会认知缺陷和社会攻击性缺陷中的重要性 因为我们发现CA2是社会再认记忆所必需的，并与社会认知记忆有关 攻击性。作为社会荷尔蒙，精氨酸加压素通过以下途径促进社会记忆和社会攻击性 增强CA2的输入和输出，并已被证明对动物癫痫发作有调节作用，我们将探讨其作用 该激素对癫痫小鼠社会行为改变的调节作用。通过评估 CA2在癫痫中，这个项目提供了对癫痫发作的基本机制洞察和 社会行为共病，并可能验证高度富含CA2神经元的新药物靶点。

PROJECT ABSTRACT A key challenge in temporal lobe epilepsy (TLE) is to determine the neural mechanisms contributing to seizures because current drugs fail to treat all seizures and usually come with debilitating side effects. Moreover, current drugs do not treat alterations in social behavior often manifest by individuals with epilepsy, including increased social aggression. This project will challenge current dogma as to the pathophysiological bases of how the hippocampus contributes to seizures in TLE, which has focused on three major regions of the hippocampus: dentate gyrus, CA3 and CA1. Instead, we examine area CA2, a relatively small region of hippocampus that has received little attention but is known to survive relatively intact in TLE patients and rodent models, and may serve as a seizure focus or facilitate seizure propagation. Experimental tools developed in the laboratories of the two Principal Investigators now enable the direct investigation of the importance of CA2 in mouse TLE models by employing a mouse line that expresses Cre recombinase relatively selectively in CA2 principal neurons. Cre-dependent viral vectors will be used to express genetically encoded tools in CA2 principal neurons to examine both alterations in CA2 circuitry in TLE and the effects of CA2 acute or chronic silencing on seizures. Thus, we will determine whether CA2 controls the pharmacological induction of acute seizures in the healthy brain and/or chronic seizures in the epileptic brain. We will also determine the importance of CA2 in reported deficits in social cognition and social aggression in mouse models of acquired TLE, as we find that CA2 is required for social recognition memory and is implicated in social aggression. As the social hormone arginine vasopressin promotes social memory and social aggression by enhancing CA2 input and output, and has been shown to regulate seizures in animals, we will examine the role of CA2 regulation by this hormone on social behavioral alterations in epileptic mice. By evaluating the role of CA2 in epilepsy, this project offers the promise of providing both basic mechanistic insight into seizures and social behavioral comorbidity, and may validate novel drug targets highly enriched in CA2 neurons.