Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease

最近的证据表明，突触传递的异常可能是脑梗死发病机制的基础。 几种神经精神疾病更好地了解正常和异常突触功能可能 提供改进的检测和治疗策略，从而减少总体疾病负担。对这些 最后，在小鼠中使用基因靶向技术提供了一个独特的机会来创造具有以下特征的实验室动物： 与临床上定义的神经精神疾病的人类患者相似的突变。深入分析 这些突变小鼠的行为和细胞水平，因此可以提供丰富的信息 疾病形成的潜在机制以及基因功能障碍与异常 行为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（SCAMs）与神经精神障碍包括自闭症的相关性， 精神分裂症和强迫症。神经连接素（NL）/神经肽复合物，一种典型的 SCAM对参与兴奋性和抑制性突触功能。为了进一步探索 NL功能，使小鼠在NL 3基因中具有点突变（R451 C）以模拟突变 与孤独症相关的研究。这项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 潜在的回路和突触异常因果关系将通过尝试改善 通过解决潜在的突触缺陷来改善行为表型。我选择专注于功能性 NL 3R 451 C突变体的认知缺陷，特别是认知灵活性，因为这些代表了一个核心， 许多神经精神疾病的特征及其潜在的突触机制迄今已收到 很少注意。初步数据表明，NL 3R 451 C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NL 3功能， 保持认知灵活性。此外，我将采用皮质传入群体的光遗传学募集， 急性切片，以探讨背侧纹状体皮质纹状体突触传递的异常， NL 3R 451 C突变小鼠。对于独立阶段，我将首先探索突触的潜在异常， NL 3R 451 C突变体的可塑性。在彻底描述了基础传输和 在突变体的纹状体中发现的活动依赖性可塑性，我将试图将这些突触缺陷与 通过使用细胞类型和区域光遗传学方法观察到的认知灵活性异常 操纵我预期这个提议将揭示关于突触基础的有趣信息 以及NL 3R 451 C突变体中突触传递的扰动如何导致认知灵活性的刚性改变。 行为输出此外，它将为我将来研究其他突触如何提供一个模板。 分子介导认知功能。

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.