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: 9069064
• 负责人: Marc V Fuccillo
• 金额: $ 23.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069064
• 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; Genetic study; 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; Obsessive-Compulsive Disorder; 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; neuropsychiatric disorder; optogenetics; postsynaptic; synaptic function; synaptogenesis; transmission process; treatment strategy

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 obsessive 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 localize 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 will 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 cell-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.

最近的证据表明，突触传递异常可能是疾病发病机制的基础 几种神经精神疾病。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。朝着这些 最终，在小鼠中使用基因打靶为创造具有以下特征的实验动物提供了独特的机会： 与患有临床定义的神经精神疾病的人类患者相似的突变。全面分析 因此，这些突变小鼠在行为和细胞水平上都可以提供有关 疾病形成的潜在机制以及基因功能障碍与异常之间的关系 行为。来自各种人类遗传关联研究的证据强调了功能性 突触细胞粘附分子（SCAM）与神经精神疾病（包括自闭症）的相关性， 精神分裂症和强迫症。 Neuroligin (NL)/Neurexin 复合物，一种典型的 SCAM 对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NL3基因中添加点突变（R451C）的小鼠以模拟突变 人类遗传学研究中与自闭症有关。该提案的目标是研究这种突变小鼠 从行为和突触的角度，希望将异常行为与特定的行为联系起来 潜在的电路和突触异常。然后将通过尝试改善来建立因果关系 通过解决潜在的突触缺陷来改变行为表型。我选择专注于功能性 NL3R451C 突变体中的认知缺陷，特别是认知灵活性，因为它们代表了核心的、使人衰弱的 迄今为止，许多神经精神疾病的特征及其潜在的突触机制已被 很少关注。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，我将采用病毒注射来定位哪些突触需要 NL3 功能 保持认知灵活性。此外，我将采用光遗传学招募皮质传入群体 急性切片探讨背侧纹状体皮质纹状体突触传递异常 NL3R451C 突变小鼠。对于独立阶段，我将首先探讨突触的潜在异常 NL3R451C 突变体的可塑性。在彻底描述了基础传输和传输的改变之后 在突变体纹状体中发现的活动依赖性可塑性，我将尝试将这些突触缺陷与 通过使用细胞类型和区域光遗传学观察到的认知灵活性异常 操纵。我预计该提案将揭示有关突触基础的有趣信息 认知灵活性的影响以及 NL3R451C 突变体中突触传递的扰动如何导致僵化 行为输出。此外，它将为我未来研究其他突触如何 分子介导认知功能。