Roles of Kainate Receptors in Compulsive-Like Behaviors

红藻氨酸受体在强迫样行为中的作用

• 批准号: 8165876
• 负责人: jian xu
• 金额: $ 12.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165876
• 关键词: Affect; Animal Model; Behavior; Biochemical; Brain; Brain region; Complement; Complex; Corpus striatum structure; Development; Disease; Equilibrium; Family; Gated Ion Channel; Genes; Genetic; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Image; Kainic Acid Receptors; Knock-out; Knockout Mice; Laser Scanning Microscopy; Ligands; Light; Mediating; Mediator of activation protein; Mental disorders; Mus; Mutant Strains Mice; Neurons; Obsessive-Compulsive Disorder; Pathogenesis; Phenotype; Play; Population; Presynaptic Terminals; Proteins; Receptor Gene; Receptor Signaling; Research Design; Role; Scaffolding Protein; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Symptoms; Synapses; Synaptic Transmission; System; Thalamic structure; Therapeutic Agents; Thinking; Viral; Work; early onset; effective therapy; insight; neural circuit; neurotransmitter release; novel; novel therapeutics; postsynaptic; presynaptic; receptor expression; research study; sensor; synaptic function; transmission process; two-photon

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a common psychiatric disorder affecting 2-3 % of the population. The causes for these disorders are not well understood, as such, effective treatments are lacking. In preliminary studies I have found that knockout of one class of the glutamate receptor family, the kainate receptors leads to OCD-like behaviors in mice. My working hypothesis is that deleting KAR impairs corticostriatal synaptic transmission, leading to robust OCD-like behavior in mice. In light of this, a better understanding of KAR's role in corticostriatal synaptic transmission will provide key insight into pathogenesis of OCD. In the proposed experiments, I will combine electrophysiological recording and two-photon laser- scanning microscopy (2PLSM), complemented with mechanistic biochemical studies to determine the function and association of synaptic kainate receptors in corticostriatal synapses. In Specific Aim 1, I will determine the contribution of kainate receptors to corticostriatal synapses. Kainate receptors can be presynaptic modulators of transmitter release or postsynaptic mediators of synaptic transmission. I will perform electrophysiological recording from spiny neurons to determine whether postsynaptic kainate receptors contribute to synaptic integration. In the second part of this aim I will determine whether presynaptic kainate receptors modulate neurotransmitter release at corticostriatal synapses. For this purpose I will make use of a novel presynaptic activity sensor (Sph4X) that we recently developed to interrogate presynaptic activity in kainate receptor knockout mice. Viral mediated transduction of cortical neurons followed by two-photon laser scanning microscopy (2PLSM) of presynaptic terminals in striatum will be used to determine whether kainate receptors modulate corticostriatal synapses. In Specific Aim 2, I will determine whether kainate receptor scaffolding protein interactions in the striatum contribute corticostriatal synaptic function. A previous study has demonstrated that loss of a scaffolding protein SAPAP3 in the striatum results in OCD like phenotype similar to that in kainate receptor knockout mice. I hypothesize that kainate receptors are stabilized at striatal synapses through an interaction with SAPAP proteins. In preliminary findings I demonstrate that kainate receptor subunits co- immunoprecipitate with SAPAP proteins from brain lysate suggesting they are in the same signaling complex. In this aim I will determine how kainate receptors interact with SAPAP and whether this interaction is important for functions of kainate receptors at striatal synapses. In summary, these studies are designed to elucidate the important roles of kainate receptors in regulating synaptic transmission at corticostriatal synapses. The use of novel animal models will provide important insight into the roles of kainate receptors in pathogenesis of OCD. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder affecting 2~3 % of total populations. In my preliminary studies I have discovered robust OCD-like behaviors in mutant mice lacking kainate receptor genes. In this proposal I will study the mechanisms of how these kainate receptors are involved in the development of OCD disorder.

描述（由申请人提供）：强迫症（OCD）是一种常见的精神疾病，影响了2- 3%的人口。这些疾病的病因尚不清楚，因此缺乏有效的治疗方法。在初步研究中，我发现敲除谷氨酸受体家族中的一类，即盐酸盐受体，会导致小鼠出现类似强迫症的行为。我的工作假设是，删除KAR会损害皮质纹状体突触传递，导致小鼠出现强烈的强迫症样行为。因此，更好地了解KAR在皮质纹状体突触传递中的作用将为强迫症的发病机制提供关键的见解。在拟议的实验中，我将结合电生理记录和双光子激光扫描显微镜（2PLSM），辅以机械生化研究来确定皮质纹状体突触中突触盐酸盐受体的功能和关联。在Specific Aim 1中，我将确定盐酸盐受体对皮质纹状体突触的贡献。盐酸盐受体可以是递质释放的突触前调节剂或突触传递的突触后调节剂。我将对棘神经元进行电生理记录，以确定突触后盐酸盐受体是否有助于突触整合。在这个目标的第二部分，我将确定突触前盐受体是否调节皮质纹状体突触的神经递质释放。为此，我将利用我们最近开发的一种新的突触前活动传感器（Sph4X）来询问海因酸盐受体敲除小鼠的突触前活动。病毒介导的皮质神经元转导以及纹状体突触前终末的双光子激光扫描显微镜（2PLSM）将用于确定海碱盐受体是否调节皮质纹状体突触。在Specific Aim 2中，我将确定纹状体中海碱盐受体支架蛋白的相互作用是否有助于皮质纹状体突触功能。先前的一项研究表明，纹状体中支架蛋白SAPAP3的缺失会导致强迫症样表型，类似于海盐酸盐受体敲除小鼠的表型。我假设蓝盐受体通过与SAPAP蛋白的相互作用稳定在纹状体突触。在初步研究结果中，我证明了海碱盐受体亚基与脑裂解液中的SAPAP蛋白共免疫沉淀，表明它们处于相同的信号复合体中。在这个目的中，我将确定盐酸盐受体如何与SAPAP相互作用，以及这种相互作用是否对纹状体突触中盐酸盐受体的功能重要。综上所述，这些研究旨在阐明蓝酸盐受体在调节皮质纹状体突触突触传递中的重要作用。新的动物模型的使用将为了解盐酸盐受体在强迫症发病机制中的作用提供重要的见解。