The role of glutamate receptors in compulsive and perseverative behavior

描述（由申请人提供）：强迫症（OCD）是一种慢性和衰弱性焦虑障碍，其特征是持续的侵入性思想、强迫、强迫和重复的习惯性行为。据估计，强迫症影响了1-2%的人口，使其成为第四大最常见的精神疾病，但目前的治疗选择和治疗方法有限，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，皮质纹状体环路中的谷氨酸能信号在异常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kainate受体（一种调节性谷氨酸受体）的基因被切除的突变小鼠出现异常行为，其特征是强迫性梳洗行为增加和焦虑增加。这种强迫性梳理和焦虑的表型与一些基因突变的小鼠相似，它们表现出强迫性的、自残的梳理行为，这些行为被认为是强迫症的小鼠模型。盐酸盐受体在纹状体中大量表达；然而，它们在调节纹状体突触和回路中的作用尚未明确。在本研究中，我们将结合电生理学、光遗传学、行为学和生物化学方法来确定盐酸盐受体在纹状体回路中的细胞作用及其对持久性行为的贡献。我们的假设是，在纹状体棘突神经元（SPNs）中，海碱盐受体信号在调节突触传递和可塑性中起作用。这种调节的丧失严重损害了条纹的输出，导致不适应的习惯和强迫行为。因此，在具体的目的1中，我们将确定海碱盐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在初步研究中发现的一种新的信号传导机制来调节SPN突触。在具体目标2中，我们将确定在纹状体中，盐酸盐受体和另一种已知的强迫症相关突触支架之间的相互作用是否调节突触盐酸盐受体的功能。在具体目标3中，我们将利用条件遗传和药理学方法来研究特定操作后的行为，从而确定小鼠强迫行为的电路基础。这些研究将共同确定纹状体中盐酸盐受体的细胞和电路作用，以及它们在强迫行为中的潜在作用。作为第一个将盐酸盐受体家族与强迫症机制联系起来的研究，这一提议将开辟新的领域，并有可能为这种衰弱性神经精神疾病的治疗策略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.