Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease

描述(由申请人提供)：最近的证据表明，突触传递的异常可能是几种神经精神障碍的基础。更好地了解正常和异常的突触功能可能会提供更好的检测和治疗策略，从而减少总体疾病负担。为了达到这些目的，在小鼠身上使用基因打靶提供了一个独特的机会，可以创造出与临床上定义为神经精神疾病的人类患者相似的突变的实验室动物。因此，在行为和细胞水平上对这些突变小鼠进行彻底分析，可以提供关于疾病形成的潜在机制以及基因功能障碍和异常行为之间的关系的丰富信息。来自各种人类遗传关联研究的证据强调了突触细胞黏附分子(SCAM)在包括自闭症、精神分裂症和强迫症在内的神经精神疾病中的功能相关性。神经连接蛋白(NL)/neuresin复合体是一对典型的SCAM，参与了兴奋性和抑制性突触功能。为了进一步探索NL的功能，在一项人类遗传学研究中，用NL3基因点突变(R451C)制造了一只小鼠，以模拟与自闭症相关的突变。这项建议的目的是从行为和突触两个角度研究这只突变小鼠，希望将异常行为与特定的潜在回路和突触异常联系起来。然后，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。我选择关注NL3R451C突变体的功能性认知缺陷，特别是认知灵活性，因为这些代表了许多神经精神障碍的核心、令人衰弱的特征，而且到目前为止，它们潜在的突触机制几乎没有受到关注。初步数据显示，NL3R451C突变严重损害了认知灵活性。在指导阶段，我将使用病毒注射来定位哪些突触需要NL3功能来保持认知灵活性。此外，我将在急性脑片上利用皮质传入群体的光遗传招募来探索NL3R451C突变小鼠背侧纹状体皮质纹状体突触传递的异常。对于独立阶段，我将首先探讨突触可塑性的潜在异常。 在NL3R451C突变体中。在彻底描述了突变体纹状体基础传递和活动依赖可塑性的变化后，我将尝试通过使用细胞类型和区域光遗传操作来将这些突触缺陷与观察到的认知灵活性异常联系起来。我预计这项提案将揭示有关认知灵活性的突触基础以及微扰如何 突触传递的NL3R451C突变体导致僵硬的行为输出。此外，它将为我未来研究其他突触分子如何调节认知功能提供一个模板。 与公共健康相关：突触是一种特殊的连接，在不同的大脑区域之间进行沟通。最近的证据表明，突触的异常可能是一系列神经精神障碍的核心。这项提案将使用尖端方法来探索突触功能障碍及其与行为改变的关系，希望能揭示神经精神疾病的原因。

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.