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老年痴呆症发病的基础。 几种神经精神障碍。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，从而减少总体疾病负担。朝向这些 最终，在小鼠身上使用基因打靶提供了一个独特的机会来创造具有 与临床定义为神经精神障碍的人类患者相似的突变。透彻分析 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的关系 行为。来自各种人类基因关联研究的证据强调了功能 突触细胞黏附分子与包括自闭症在内的神经精神障碍的相关性 精神分裂症和强迫症。神经连接蛋白(NL)/Neuresin复合体--一个原型 SCAM对与兴奋性和抑制性突触功能有关。为了进一步探索 为了研究NL功能，用NL3基因点突变(R451C)来模拟突变 在人类遗传学研究中与自闭症有关。这项提议的目标是研究这种突变的小鼠 从行为和突触的角度来看，希望将异常行为与特定的 潜在的回路和突触异常。然后将通过试图改善的方式来确定因果关系 通过解决潜在的突触缺陷来实现行为表型。我选择将重点放在功能上 NL3R451C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，使人衰弱 到目前为止，许多神经精神障碍的特征及其潜在的突触机制 很少有人注意到。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，我将在大脑皮层传入群体中采用光基因招募 大鼠纹状体背侧皮质纹状体突触传递异常的急性切片研究 NL3R451C突变小鼠。在独立阶段，我将首先探讨突触的潜在异常 NL3R451C突变体的可塑性。在详细描述了基本变速器和 在突变体的纹状体中发现的活性依赖的可塑性，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观察到的认知灵活性异常 操纵。我预计这项提案将揭示有关突触基础的有趣信息。 NL3R451C突变体的认知灵活性以及突触传递的扰动如何导致僵硬 行为输出。此外，它将为我未来研究其他突触如何 分子调节认知功能。

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.