Frontostriatal Synaptic Dysfunction in a Model of Autism

描述(由申请人提供)：这项建议的目的是促进我们对自闭症谱系障碍(ASDS)的有限病理生理学的理解，ASDS是一组普遍和破坏性的神经精神疾病。这将通过研究携带基因突变(神经连接蛋白-3R451C)的小鼠来实现，该突变是高度渗透性的，并与人类的自闭症特异相关。初步数据表明，这些小鼠在运动学习任务中发展出更自动化和刻板的行为，这种表型可能代表行为指标，因为它也与其他与ASD相关的基因突变有关。我建议研究纹状体及其来自额叶皮质的突触输入的功能，这是一个可能导致上述行为变化的神经回路，以及与自闭症相关的其他形式的僵硬和习惯性行为。利用光遗传学对光刺激这一神经回路，将在神经连接蛋白-3R451C突变小鼠中检测额纹状体突触的功能特性。初步数据表明，这种方法在脑片制备中检测突触功能是可行的。额纹状体突触经历活动依赖性可塑性的能力也将被评估。最后，在对神经连接蛋白-3在这个神经回路中的表达进行分子操作后，将检查生理和行为。总而言之，这些实验试图确定突变基因及其产物(神经连接蛋白-3 R451C)影响额纹状体回路功能的机制，结合使用多种大脑功能(分子、细胞、回路和行为)的实验方法。

DESCRIPTION (provided by applicant): The objective of this proposal is to advance our limited understanding of the pathophysiology of autism spectrum disorders (ASDs), a group of prevalent and devastating neuropsychiatric conditions. This will be accomplished by studying mice carrying a genetic mutation (neuroligin-3 R451C) that is highly penetrant and specifically associated with ASDs in humans. Preliminary data indicate these mice develop more automated and stereotyped behavior in a motor learning task, a phenotype that may represent a behavioral indicator, as it is also associated with other ASD-related genetic mutations. I propose to investigate the function of the striatum and its synaptic inputs from frontal cortex, a neural circuit that may contribute to the aforementioned behavioral change, as well as other forms of inflexible and habitual behavior associated with ASDs. Using optogenetics to specifically stimulate this neural circuit with light, the functional properties of frontostriatal synapses will be examined in neuroligin-3 R451C mutant mice. Preliminary data indicates the feasibility of this approach for assaying synaptic function in a brain slice preparation. The capacity of frontostriatal synapses to undergo activity-dependent plasticity will also be assessed. Finally, physiology and behavior will be examined following molecular manipulation of neuroligin-3 expression within this neural circuit. In total, these experiments attempt to determine the mechanism by which mutated gene and its product (neuroligin-3 R451C) influence the function of frontostriatal circuits, using a combination of experimental approaches that integrate multiple levels of brain function (molecules, cells, circuits and behavior).