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异常可能是几种神经精神疾病发病机制的基础。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，从而减少整体疾病负担。为了实现这些目标，在小鼠中使用基因靶向提供了一个独特的机会，可以创建具有与临床定义的神经精神疾病的人类患者相似突变的实验动物。因此，从行为和细胞水平对这些突变小鼠进行深入分析，可以为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提供丰富的信息。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（SCAMs）在神经精神疾病（包括自闭症、精神分裂症和强迫症）中的功能相关性。神经素(NL)/Neurexin复合物是一类典型的SCAM复合物，与兴奋性和抑制性突触功能有关。为了进一步探索NL的功能，研究人员在NL3基因上制造了一个点突变（R451C）的小鼠，以模仿人类遗传学研究中与自闭症相关的突变。本研究的目标是从行为和突触两个角度研究这种突变小鼠，希望将异常行为与特定的底层电路和突触异常联系起来。然后，通过解决潜在的突触缺陷，试图改善行为表型，从而建立因果关系。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，因为这些是许多神经精神疾病的核心衰弱特征，其潜在的突触机制迄今为止很少受到关注。初步数据表明，NL3R451C突变体严重损害认知灵活性。在辅导阶段，我将对需要NL3功能来维持认知灵活性的局部突触进行病毒注射。此外，我将在急性切片中使用皮质传入群的光遗传学募集来探索NL3R451C突变小鼠背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

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.