Striatal synaptic Abnormalities in Models of Autism

自闭症模型中的纹状体突触异常

基本信息

批准号：
8848888
负责人：
Craig M Powell
金额：
$ 39.75万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848888
关键词：
Address Affect Agonist Animal Model Autistic Disorder Behavior Behavioral Brain Brain region Cell Adhesion Cell Adhesion Molecules Characteristics Communication Copy Number Polymorphism Corpus striatum structure Cutaneous Cycloserine Data Diagnostic Disease Dissection Dorsal Exhibits Functional disorder Future Gene Deletion Gene Family Genes Genetic Genetic Models Gilles de la Tourette syndrome Glutamates Goals Grooming Human Hydroxyl Radical Hyperactive behavior Isoxazoles Knock-out Knockout Mice Lead Light Link Mediating Medical Genetics Modeling Molecular Abnormality Motor Movement Disorders Mus Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Neurosciences Obsessive compulsive behavior Obsessive-Compulsive Disorder Pathologic Pathway interactions Patients Pattern Peripheral Nerves Phenotype Physiology Property Propionates Proteins Publishing Reversal Learning Rodent Role Social Interaction Stereotyped Behavior Stereotyping Symptoms Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing Translating Trichotillomania Work autism spectrum disorder base glycine transporter insight interest member mouse model neural circuit neuroligin 1 novel postsynaptic density protein receptor receptor function research study social communication synaptic function tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. We have created a novel autism model mouse line based on deletion of neuroligin-1. These mice have selective, excessive repetitive behavioral abnormalities of potential relevance to autism. Our preliminary data strongly implicate a decrease in NMDA receptor function in the striatum as a cause of this repetitive behavior phenotype. We now propose experiments to examine the effect of deletion of this gene on cortico-striatal synaptic function in detail. Furthermore, we propose to selectively rescue/treat this phenotype using genetic and pharmacologic approaches. Thus, we will be able to directly connect a specific synapse in a specific brain region due to a specific molecular abnormality with an abnormal behavior, an important basic goal in neuroscience. These experiments will identify novel synaptic and circuit-level mechanisms for obsessive-compulsive disorder- like repetitive behaviors in general. In addition, we hope to identify novel treatment targets for these behaviors for a subset of autistic patients.

描述（由申请人提供）：自闭症谱系障碍（ASD）是常见的，使影响社会互动，沟通和重复行为的疾病令人衰弱。最近的遗传发现已将突触细胞粘附基因和基因编码其相互作用的蛋白质伴侣在中央突触的基因中鉴定为自闭症谱系疾病的遗传原因。我们基于神经素1的缺失创建了一种新型的自闭症模型小鼠系。这些小鼠具有与自闭症的潜在相关性的选择性，过度重复的行为异常。我们的初步数据强烈暗示纹状体中NMDA受体功能的降低是这种重复行为表型的原因。现在，我们提出了实验，以详细研究该基因缺失对皮质 - 纹状体突触功能的影响。此外，我们建议使用遗传和药理方法选择性地挽救/治疗此表型。因此，由于特定的分子异常和异常行为，我们将能够直接连接特定大脑区域的特定突触，这是神经科学的重要基本目标。这些实验将确定一种新型的突触和电路水平机制，用于强迫症（例如重复性行为）。此外，我们希望确定自闭症患者一部分这些行为的新型治疗目标。