Roles of SAPAP Proteins in Synaptic Function and Compulsive-like Behavior

SAPAP 蛋白在突触功能和强迫样行为中的作用

• 批准号: 7805467
• 负责人: Guoping Feng
• 金额: $ 37.69万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-16 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805467
• 关键词: Actins; Affect; Anxiety; Applications Grants; Behavior; Behavioral; Biochemical; Brain; Brain imaging; Brain region; Complex; Corpus striatum structure; Cytoskeleton; DLG4 gene; Data; Defect; Development; Disease; Docking; Electrophysiology (science); Excitatory Synapse; Face; Family; Functional disorder; Gene Family; Genes; Genetic; Grooming; Hair Removal; Lesion; Macromolecular Complexes; Mediating; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Mutation; Nervous System Physiology; Neurons; Neurotransmitter Receptor; Obsessive-Compulsive Disorder; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Postsynaptic Membrane; Protein Family; Proteins; Proteomics; Receptor Signaling; Relative (related person); Role; SAP90 protein; Scaffolding Protein; Selective Serotonin Reuptake Inhibitor; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Staging; Subfamily lentivirinae; Synapses; Tamoxifen; Testing; Thalamic structure; Transgenic Mice; base; density; in vivo; insight; member; mutant; nervous system disorder; neural circuit; neuropsychiatry; neuropsychological; postsynaptic; recombinase; scaffold; selective expression; skin lesion; synaptic function; therapeutic target

DESCRIPTION (provided by applicant): Precise synaptic connectivity is essential for the proper function of the nervous system and defects are implicated in many neurological disorders. However, the mechanisms regulating the assembly and function of synapses in vivo are still poorly understood. As a first step toward understanding the in vivo function of key scaffolding proteins at excitatory synapses we initiated a molecular genetic study on SAP90/PSD95 associated proteins (SAPAPs). SAPAP family proteins (SAPAP1-4) were originally identified as proteins interacting with PSD95 family and Shank family proteins, two other major multidomain scaffolding proteins at excitatory synapses. Together these three groups of proteins have been proposed to form a key scaffolding complex to anchor/target neurotransmitter receptors and signaling molecules to the postsynaptic membrane of excitatory synapses. We found that SAPAP family proteins are widely, yet differentially expressed in the brain. They are highly enriched in the postsynaptic density, and exclusively expressed at excitatory synapses, consistent with their proposed role in postsynaptic scaffolding. In this grant application we propose to combine genetic, biochemical, electrophysiological and behavioral approaches to determine the role of SAPAPS in synaptic development and function, and its implication in obsessive compulsive disorder (OCD)-like behavior. SAPAPS is the only member of the SAPAP gene family that is highly expressed in the striatum, a major brain region involved in pathogenesis of OCD spectrum disorders. We found that genetic deletion of SAPAPS gene in mice results in compulsive grooming behavior leading to facial hair removal and skin lesions, accompanied by significantly increased anxiety. Furthermore, both biochemical and electrophysiological studies reveal cortico-striatal synaptic defects in the mutant mice. These data strongly suggest that SAPAPS plays an important role at cortico-striatal synapses, and thus provide us a unique opportunity to dissect the synaptic mechanisms leading to the development of OCD-like behavior in mice. Obsessive-compulsive disorder is the second most prevalent neuropsychiatric disease, affecting ~2% of the population. This study will use the power of mouse genetics to determine how defects in neuronal connectivity may contribute to the pathogenesis of obsessive-compulsive disorder.

描述（由申请人提供）：精确的突触连接对于神经系统的正常功能是必不可少的，并且缺陷与许多神经系统疾病有关。然而，调节突触在体内的组装和功能的机制仍然知之甚少。作为了解兴奋性突触关键支架蛋白体内功能的第一步，我们启动了SAP 90/PSD 95相关蛋白（SAPAPs）的分子遗传学研究。SAPAP家族蛋白（SAPAP 1 -4）最初被鉴定为与PSD 95家族和Shank家族蛋白相互作用的蛋白质，这两个家族是兴奋性突触中的另外两个主要多结构域支架蛋白。已经提出这三组蛋白质一起形成关键的支架复合物，以将神经递质受体和信号分子锚/靶向兴奋性突触的突触后膜。我们发现SAPAP家族蛋白在大脑中广泛但差异表达。它们在突触后密度中高度富集，并且仅在兴奋性突触中表达，这与它们在突触后支架中的作用一致。在这项资助申请中，我们建议结合联合收割机遗传学，生物化学，电生理学和行为学的方法来确定SAPAPS在突触发育和功能中的作用，以及其在强迫症（OCD）样行为中的意义。SAPAPS是SAPAP基因家族中唯一在纹状体中高度表达的成员，纹状体是参与OCD谱系障碍发病的主要脑区。我们发现，SAPAPS基因在小鼠中的遗传缺失导致强迫性梳理行为，导致面部脱毛和皮肤损伤，并伴有显著增加的焦虑。此外，生物化学和电生理研究揭示了突变小鼠的皮质-纹状体突触缺陷。这些数据有力地表明，SAPAPS在皮质-纹状体突触中起着重要的作用，从而为我们提供了一个独特的机会来解剖导致小鼠OCD样行为发展的突触机制。强迫症是第二大流行的神经精神疾病，影响约2%的人口。这项研究将利用小鼠遗传学的力量来确定神经元连接缺陷如何导致强迫症的发病机制。