Kainate receptor signaling in striatal synaptic function and plasticity

描述(申请人提供)：强迫症(OCD)是一种慢性焦虑症，以过度打扮、囤积或检查等不适应的强迫行为为特征。强迫症是一种使人衰弱的疾病，估计影响到1%-2%的人口，使其成为仅次于抑郁症、酒精中毒和社交焦虑障碍的第四大常见精神疾病。尽管在药理学、行为学和外科治疗方面有所创新，但至少有30%的病例被证明是难以治愈的。最近在了解强迫症神经生物学基础方面的进展突显了纹状体皮质下区域谷氨酸系统功能障碍的核心作用。谷氨酸系统是大脑的主要兴奋性神经递质。除了将强迫症与纹状体活动改变联系在一起的临床文献外，AIMA研究还表明，皮质神经元与纹状体棘突投射神经元(SPN)形成的突触在调节习惯形成方面至关重要。这一一致的证据表明，正常纹状体活动的扰动将对于理解强迫症患者中出现的不适应强迫、习惯性行为至关重要。缺乏海人酸受体(谷氨酸受体的一种亚型)表达的小鼠，会有一种戏剧性的强迫性梳理和焦虑表型，这让人想起强迫症。尽管海人藻酸受体在纹状体高表达，但尚不清楚海人藻酸受体如何参与纹状体突触传递和可塑性，从而对纹状体环路的整体调控起作用。初步工作已经确定，在纹状体中，激活海人藻酸受体有助于 释放内源性大麻素。这是一种以前从未被演示过的新颖的相互作用。内源性大麻素是一种常见的神经调节剂，可以下调整个大脑突触的递质释放。我推测，这种海人藻酸受体与内源性大麻素的偶联提供了一种生理上相关的方法来调节纹状体内谷氨酸的释放，这对海人藻酸受体基因敲除小鼠的行为表型非常重要。以下目的旨在确定红藻氨酸受体与内源性大麻素偶联的生化机制，以及这种相互作用对正常纹状体突触功能和可塑性的贡献。 公共卫生相关性：强迫症(OCD)是一种衰弱疾病，其特征是适应不良、强迫或习惯性行为，估计影响1-2%的人口。我们开发了一种新的强迫症小鼠模型，以帮助阐明特定脑区突触传递的变化如何导致习惯性行为。虽然目前30%的强迫症病例是难治性的，但了解这些生化和突触异常将导致更有效、更特异的治疗，并产生更少的并发症。

DESCRIPTION (provided by applicant): Obsessive Compulsive Disorder (OCD) is a chronic anxiety disorder characterized by maladaptive compulsive behavior such as excessive grooming, hoarding or checking. OCD is a debilitating disease, estimated to affect 1-2% of the population, making it the fourth most common mental illness after depression, alcoholism and social anxiety disorder. Despite innovations in pharmacological, behavioral, and surgical treatments at least 30% of cases prove intractable. Recent advances in understanding the neurobiological underpinnings of OCD have highlighted a central role for dysfunction of the glutamate system, the brain's major excitatory neurotransmitter, in the subcortical region of the striatum. In addition to clinical literature linking OCD to alterations in striatal activity, anima studies have indicated that the synapses formed by cortical neurons onto striatal spiny projection neurons (SPNs) are crucial in regulating habit formation. This convergent evidence indicates that perturbations in normal striatal activity will be crucial to understanding the emergence of maladaptive compulsive, habitual behavior seen in patients with OCD. Mice lacking expression of the kainate receptor, a subtype of glutamate receptor, have a dramatic compulsive grooming and anxiety phenotype reminiscent of that seen in OCD. Despite being highly expressed in the striatum, it is not known how kainate receptors contribute to striatal synaptic transmission and plasticity, and therefore to the overall regulation of the striatal circut. Preliminary work has determined that, in the striatum, activating kainate receptors facilitates the release of endocannabinoids. This is a novel interaction that has not been previously demonstrated. Endocannabinoids are common neuromodulators that serve to down-regulate transmitter release at synapses throughout the brain. I hypothesize that this coupling of kainate receptors to endocannabinoids provides a physiologically relevant method of regulating glutamate release in the striatum that is highly important for the behavioral phenotype of kainate receptor knockout mice. The following aims propose to determine the biochemical mechanism by which kainate receptors couple to endocannabinoids and the contribution of this interaction to normal striatal synaptic function and plasticity. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive Disorder (OCD) is a debilitating disease characterized by maladaptive compulsive or habitual behavior that is estimated to affect 1-2% of the population. We have developed a novel mouse model of OCD to help elucidate how changes in synaptic transmission in specific brain regions give rise to habitual behavior. While currently 30% of OCD cases are intractable, understanding these biochemical and synaptic abnormalities will lead to treatments that are more effective, specific, and give rise to fewer complications.