Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease

将神经精神疾病模型中的突触和认知缺陷联系起来

• 批准号: 8424086
• 负责人: Marc V Fuccillo
• 金额: $ 8.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424086
• 关键词: Acute; Address; Adhesions; Afferent Pathways; Attention; Autistic Disorder; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cell Adhesion Molecules; Cognitive; Cognitive deficits; Communication; Complex; Corpus striatum structure; DRD2 gene; Data; Defect; Detection; Disease; Dorsal; Electrophysiology (science); Environment; Etiology; Excitatory Synapse; Focal Adhesions; Functional disorder; Future; Gene Targeting; Genes; Genetic; Glutamate Receptor; Goals; Grant; Hippocampus (Brain); Human; Human Genetics; Individual; Injection of therapeutic agent; Intervention; Knowledge; Laboratory Animals; Learning; Leucine-Rich Repeat; Ligands; Light; Link; Literature; Long-Term Depression; Maintenance; Medial; Mediating; Mediator of activation protein; Mentors; Methodology; Modeling; Molecular Analysis; Mus; Mutant Strains Mice; Mutation; Neurons; Nucleus Accumbens; Output; Pathogenesis; Patients; Phase; Phenotype; Point Mutation; Population; Prefrontal Cortex; Recruitment Activity; Reversal Learning; Role; Scaffolding Protein; Schizophrenia; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Tertiary Protein Structure; Testing; Training; Viral; Work; base; burden of illness; cell type; cognitive function; cognitive rigidity; cost; executive function; flexibility; genetic association; genetic linkage; improved; interest; mutant; neural circuit; neuropsychiatry; optogenetics; postsynaptic; synaptic function; synaptogenesis; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Recent evidence suggests that abnormalities in synaptic transmission may underlie the pathogenesis of several neuropsychiatric disorders. A better understanding of normal and aberrant synaptic function may provide improved detection and treatment strategies, thereby reducing overall disease burden. Towards these ends, the use of gene targeting in mouse has provided a unique opportunity to create laboratory animals with similar mutations to human patients that have clinically defined neuropsychiatric disorders. Thorough analysis of these mutant mice, both at the behavioral and cellular level, can thus provide a wealth of information about potential mechanisms of disease formation as well as the relationship between gene dysfunction and abnormal behavior. Evidence from a variety of human genetic association studies has highlighted the functional relevance of synaptic cell adhesion molecules (SCAMs) in neuropsychiatric disorders including autism, schizophrenia and obsesive compulsive disorder. The Neuroligin (NL)/Neurexin complex, a prototypical SCAM pair, has been implicated in excitatory and inhibitory synaptic function. In an attempt to further explore NL function, a mouse was made with a point mutation (R451C) in the NL3 gene to mimic a mutation associated with autism in a human genetics study. The goal of this proposal is to study this mutant mouse from both behavioral and synaptic perspectives, with the hope of linking abnormal behaviors to specific underlying circuit and synaptic abnormalities. Causality will then be established through attempts to ameliorate behavioral phenotypes by addressing the underlying synaptic deficits. I have chosen to focus on functional cognitive deficits, particularly cognitive flexibility, in NL3R451C mutants, as these represent a core, debilitating feature of many neuropsychiatric disorders and their underlying synaptic mechanisms have thus far received little attention. Preliminary data suggest that NL3R451C mutants have severely impaired cognitive flexibility. During the mentored phase, I will employ viral injections to localie which synapses require NL3 function to maintain cognitive flexibility. In addition, I will employ optogenetic recruitment of cortical afferent populations in the acute slice to explore abnormalities of corticostriatal synaptic transmission in the dorsal striatum of NL3R451C mutant mice. For the independent phase, I wil first explore potential abnormalities in synaptic plasticity in NL3R451C mutants. After a thorough description of the alterations of both basal transmission and activity-dependent plasticity found in the striatum of mutants, I will attempt to link these synaptic deficiencies to the observed abnormalities in cognitive flexibility through the use of cel-type and regional optogenetic manipulations. I anticipate that this proposal will uncover interesting information regarding the synaptic basis of cognitive flexibility and how perturbations of synaptic transmission in NL3R451C mutants result in rigid behavioral output. Furthermore, it will provide a template for my future studies into how other synaptic molecules mediate cognitive function. PUBLIC HEALTH RELEVANCE: Synapses are specialized junctions that mediate communication between different brain regions. Recent evidence suggests that abnormalities of the synapse may be central to a range of neuropsychiatric disorders. This proposal will use cutting-edge methodologies to explore synaptic dysfunction and its relationship to altered behavior in hopes of shedding light on the causes of neuropsychiatric disease.

描述（由申请人提供）：最近的证据表明，突触传播的异常可能是几种神经精神疾病的发病机理的基础。更好地了解正常和异常的突触功能可能会提供改进的检测和治疗策略，从而减轻总体疾病负担。在这些目的方面，在小鼠中使用基因靶向，为创建与具有临床定义神经精神疾病的人类患者相似的突变的实验动物提供了独特的机会。因此，在行为和细胞水平上对这些突变小鼠的彻底分析可以提供有关疾病形成的潜在机制以及基因功能障碍与异常行为之间的关系的大量信息。来自各种人类遗传关联研究的证据强调了突触细胞粘附分子（SCAM）在神经精神疾病中的功能相关性，包括自闭症，精神分裂症和观察性强迫症。神经素（NL）/Neurexin复合物是一种原型骗局，与兴奋性和抑制性突触功能有关。为了进一步探索NL功能，在人类遗传学研究中，在NL3基因中用点突变（R451C）制成小鼠，以模仿与自闭症相关的突变。该提案的目的是从行为和突触的角度研究这种突变小鼠，希望将异常行为与特定的基础电路和突触异常联系起来。然后，将通过尝试通过解决潜在的突触缺陷来改善行为表型来确定因果关系。我选择专注于NL3R451C突变体中的功能性认知缺陷，尤其是认知灵活性，因为这些代表了许多神经精神疾病的核心，使人衰弱的特征及其潜在的突触机制迄今未受关注。初步数据表明，NL3R451C突变体严重损害了认知灵活性。在指导阶段，我将向Localie使用病毒注射，这需要NL3功能来维持认知灵活性。此外，我将采用急性切片中皮质传入种群的光遗传学募集来探索NL3R451C突变小鼠背侧纹状体中皮质纹状体突触传播的异常。对于独立阶段，我将首先探索突触可塑性的潜在异常 在NL3R451C突变体中。在对突变体纹状体中基础传播和活性依赖性可塑性的改变进行了详尽的描述之后，我将尝试通过使用CEL型和区域光学遗传操纵来将这些突触不足与认知灵活性的异常相关。我预计该建议将发现有关认知灵活性的突触基础以及如何扰动的有趣信息 NL3R451C突变体中突触传播导致僵化的行为输出。此外，它将为我未来的研究提供一个模板，以研究其他突触分子如何介导认知功能。 公共卫生相关性：突触是介导不同大脑区域之间交流的专门连接。最近的证据表明，突触的异常可能是一系列神经精神疾病的核心。该建议将使用尖端的方法来探索突触功能障碍及其与行为改变的关系，以期阐明神经精神病的原因。