The role of glutamate receptors in compulsive and perseverative behavior

描述(申请人提供)：强迫症(OCD)是一种慢性和衰弱的焦虑症，其特征是持续的侵入性想法、强迫症、强迫和重复的习惯性行为。据估计，它影响了1-2%的人口，使其成为第四种最常见的精神疾病，但目前的治疗选择和疗法有限，许多强迫症患者对一线治疗没有反应。有相当多的证据表明，谷氨酸能信号参与皮质-纹状体环路，在异常的行为抑制和不适当的强迫或习惯性行为中起直接作用。在初步实验中，我们发现编码海人酸受体(一种可调节的谷氨酸受体)基因被去除的突变小鼠有异常行为，其特征是强迫性梳毛增加和焦虑增加。这种强迫的梳理和焦虑的表型与几个表现出强迫的、自我伤害的梳理行为的遗传小鼠突变株相似，这些突变株被认为是强迫症的小鼠模型。海人藻酸受体在纹状体中大量表达，但它们在调节纹状体突触和环路中的作用尚不清楚。在这个提案中，我们将采用电生理、光遗传学、行为学和生化相结合的方法来确定海人藻酸受体在纹状体环路中的细胞作用及其对持久化行为的贡献。我们的假设是，纹状体棘突投射神经元(SPN)中的红藻氨酸受体信号在调节突触传递和可塑性中发挥作用。失去这种调节会严重损害纹状体的输出，并导致不适应的习惯性和强迫行为。因此，在特定的目标1中，我们将确定红藻氨酸受体对纹状体突触功能和可塑性的贡献，并测试它们是否通过我们初步研究中发现的一种新的信号机制来调节SPN突触。在特定的目标2中，我们将确定海人藻酸受体与另一个已知的强迫症相关突触支架之间的相互作用是否调节纹状体中突触海人酸受体的功能。在特定目标3中，我们将利用条件遗传学和药理学方法来研究特定操作后的行为，以确定小鼠强迫行为的电路基础。总之，这些研究将确定纹状体中红藻氨酸受体的细胞和回路作用，以及它们在强迫行为中的潜在作用。这项提议将作为第一个将红藻氨酸受体家族与强迫症机械联系起来的新领域，并可能为这种衰弱的神经精神疾病的治疗策略的设计提供一个新的可接近的靶点。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a chronic and debilitating anxiety disorder characterized by persistent intrusive thoughts, obsessions, compulsions, and repetitive habitual actions. It is estimated to affect 1-2% of the population, making it the fourth most common mental illness, yet current treatment options and therapies are limited and many OCD patients are unresponsive to first-line treatment. There is considerable evidence for the involvement of glutamatergic signaling in the cortico-striatal loop having a direct role in the abnormal behavioral inhibition and inappropriate compulsive or habitual actions symptomatic of the disorder. In preliminary experiments we found that mutant mice in which the genes encoding for kainate receptors, a modulatory glutamate receptor, are ablated have abnormal behaviors marked by elevated compulsive grooming and increased anxiety. This compulsive grooming and anxiety phenotype parallels that seen with several genetic mouse mutant strains displaying obsessive, self-injurious grooming behavior that have been proposed as mouse models of OCD. Kainate receptors are abundantly expressed in the striatum; however, their roles in regulating striatal synapses and circuits have not been defined. In this proposal we will take combined electrophysiological, optogenetic, behavioral and biochemical approaches to determine the cellular roles of kainate receptors in striatal circuits and their contribution to perseverative behaviors. Our hypothesis is that kainate receptor signaling in striatal spiny projection neurons (SPNs) plays a role in regulating synaptic transmission and plasticity. Loss of this regulation significantly impairs the output of the striatm and results in the maladaptive habitual and compulsive behavior. Thus, in specific aim 1 we will determine the contribution of kainate receptors to striatal synaptic function and plasticity ad test whether they regulate SPN synapses through a novel signaling mechanism discovered in our preliminary studies. In specific aim 2 we will determine whether interaction between kainate receptors and another known OCD-associated synaptic scaffold regulates synaptic kainate receptor function in the striatum. In specific aim 3 we will determine the circuit basis for compulsive behavior in mice by utilizing conditional genetic and pharmacological approaches to study behavior after specific manipulations. Together these studies will determine the cellular and circuit roles for kainate receptors in the striatum and their potential role in compulsive behaviors. This proposal will break new ground as the first to mechanistically associate the kainate receptor family to OCD, and to potentially provide a novel approachable target for the design of therapeutic strategies for this debilitating neuropsychiatric disorder.