Frontostriatal Synaptic Dysfunction in a Model of Autism

自闭症模型中的额纹状体突触功能障碍

基本信息

批准号：
8627048
负责人：
Patrick Rothwell
金额：
$ 5.31万
依托单位：
STANFORD UNIVERSITY
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：
2012-03-01 至 2015-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627048
关键词：
Acute Arginine Autistic Disorder Automation Behavior Behavioral Biological Assay Brain Brain Part Cell Adhesion Molecules Cells Clinical Corpus striatum structure Cysteine Data Development Endocannabinoids Excitatory Synapse Exhibits Face Family Functional disorder Gene Mutation Generations Genes Genetic Habits Human Knockout Mice Lead Learning Light Link Long-Term Depression Measures Mediating Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Neurons Operative Surgical Procedures Optics Pathway interactions Patients Penetrance Phenotype Physiology Positioning Attribute Preparation Primates Process Property Protocols documentation Recombinants Research Resistance Slice Stereotyped Behavior Subfamily lentivirinae Symptoms Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Training Transgenic Mice Transgenic Organisms Validation Viral autism spectrum disorder career frontal lobe in vivo member motor learning mouse genome mouse model multidisciplinary neural circuit neuroligin 3 neuropsychiatry new therapeutic target novel optogenetics pre-clinical presynaptic prevent protein expression putamen red fluorescent protein research study stereotypy synaptic function

项目摘要

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).

描述（由申请人提供）：该提案的目的是增进我们对自闭症谱系障碍（ASD）病理生理学的有限理解，自闭症谱系障碍是一组普遍存在且具有破坏性的神经精神疾病。这将通过研究携带基因突变 (neuroligin-3 R451C) 的小鼠来实现，该突变具有高度渗透性，并且与人类自闭症谱系障碍 (ASD) 特别相关。初步数据表明，这些小鼠在运动学习任务中表现出更加自动化和刻板的行为，这种表型可能代表行为指标，因为它也与其他自闭症谱系障碍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，额叶皮层是一种神经回路，可能有助于上述行为变化，以及与自闭症谱系障碍相关的其他形式的僵化和习惯行为。使用光遗传学用光特异性刺激该神经回路，将在 Neuroligin-3 R451C 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在脑切片制备中测定突触功能的可行性。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，对该神经回路内的 Neuroligin-3 表达进行分子操作后，将检查生理学和行为。总的来说，这些实验试图确定突变基因及其产物（neuroligin-3 R451C）影响额纹状体回路功能的机制，使用整合多个水平的脑功能（分子、细胞、回路和行为）。