Frontostriatal Synaptic Dysfunction in a Model of Autism

描述（由申请人提供）：本提案的目的是促进我们对自闭症谱系障碍（ASD）病理生理学的有限了解，自闭症谱系障碍是一组普遍且毁灭性的神经精神疾病。这将通过研究携带基因突变（神经连接素-3 R451 C）的小鼠来实现，该基因突变是高度渗透性的，并且与人类的ASD特异性相关。初步数据表明，这些小鼠在运动学习任务中发展出更多的自动化和刻板行为，这是一种可能代表行为指标的表型，因为它也与其他ASD相关的基因突变有关。我建议研究纹状体的功能及其来自额叶皮层的突触输入，这是一种可能导致上述行为变化的神经回路，以及与ASD相关的其他形式的不灵活和习惯性行为。使用光遗传学来用光特异性地刺激该神经回路，将在神经连接素-3 R451 C突变小鼠中检查额纹状体突触的功能特性。初步数据表明，这种方法的可行性，在脑切片制备测定突触功能。还将评估额纹状体突触进行活动依赖性可塑性的能力。最后，生理学和行为将被检查后，神经连接素-3表达在这个神经回路的分子操作。总的来说，这些实验试图确定突变基因及其产物（神经连接素-3 R451 C）影响额纹状体回路功能的机制，使用整合多个脑功能水平（分子、细胞、回路和行为）的实验方法的组合。

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).