权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuroligin Function in vivo: Implications for Autism and Mental Retardation

Neuroligin 体内功能：对自闭症和智力迟钝的影响

基本信息

批准号：
7573138
负责人：
Craig M Powell
金额：
$ 39.25万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-23 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7573138
关键词：
Acute Address Affect Animal Model Attention Autistic Disorder Automobile Driving Behavior Behavioral Behavioral Paradigm Binding Cell Adhesion Molecules Clinical Data Deletion Mutation Disease Dose Equilibrium Exhibits FMR1 Family Figs - dietary Follow-Up Studies Fragile X Syndrome Frequencies Future Genes Genetic Genetic Models Hippocampus (Brain)Human Human Genetics Incidence Individual Inhibitory Synapse Integral Membrane Protein Knock-out Knockout Mice Learning Link Measurement Measures Mental Retardation Methods Modeling Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neocortex Neurons Output Pathogenesis Patients Phenotype Physiological Picrotoxin Protein Binding Protocols documentation Publishing Rett Syndrome Role Slice Social Behavior Social Interaction Stimulus Synapses Synaptic plasticity Syndrome Testing To specify autism spectrum disorder base cognitive function gain of function human disease in vivo loss of function mutation member mouse model mutant neurobehavioral novel postsynaptic presynaptic public health relevance research study synaptic function

项目摘要

DESCRIPTION (provided by applicant): Loss-of-function mutations in members of the neuroligin (NL) family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Animal models of autism have been severely limited, but these human genetic findings provide a novel path to develop bona fide mouse models of at least a subtype of human autism or mental retardation. NLs are postsynaptic transmembrane proteins that bind presynaptic beta-neurexins to induce formation of excitatory and inhibitory synapses and to control excitatory/inhibitory (E/I) synapse balance in cultured neurons. Alterations in E/I balance have been proposed as important in pathogenesis of autism and mental retardation. The precise role of NL in vivo and in neurobehavioral abnormalities in autism and mental retardation, however, remains to be determined. We will determine the role of neuroligin in vivo using electrophysiologic and behavioral characterization of NL knockout, human disease mutation knockin, and, in follow-up studies, conditional knockout mice. The driving hypothesis is that mice deficient in NL genes, or carrying known disease-linked mutations in NL, will exhibit behavioral differences consistent with those in human autism or mental retardation, and that these behavioral differences will be associated with specific abnormalities in E/I balance or synaptic function in cortical circuits in vivo. The following specific aims will be addressed: 1. To determine whether NL3 disease-linked mutation or deletion of NL3 result in autism and mental retardation-related behavioral abnormalities. 2. To determine whether deletion of NL3 or NL3 disease-linked mutations result in altered excitatory and inhibitory synaptic connectivity and function. 3. To determine whether deletion of NL3 or NL3 disease-linked mutations alter the threshold for inducing NMDA-receptor-dependent synaptic plasticity in the hippocampus. PUBLIC HEALTH RELEVANCE: Autism spectrum disorder and mental retardation are common, debilitating disorders involving social interaction or cognitive function with clinical overlap in a subset of patients. Recently, loss-of-function mutations in members of the Neuroligin family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Mice with genetic alterations of Neuroligin will be characterized as potential animal models of autism and mental retardation in an effort to better understand the cause and treatment of these debilitating disorders.

描述（由申请人提供）：跨突触细胞粘附分子的神经肽（NL）家族成员的功能丧失突变与人类自闭症和智力迟钝有关。自闭症动物模型受到严重限制，但这些人类遗传学发现为开发至少一种人类自闭症或智力迟钝亚型的真正小鼠模型提供了一条新途径。 NL 是突触后跨膜蛋白，可结合突触前 β-神经毒素，诱导兴奋性和抑制性突触的形成，并控制培养神经元中的兴奋性/抑制性 (E/I) 突触平衡。 E/I 平衡的改变被认为在自闭症和智力低下的发病机制中很重要。然而，NL 在体内以及在自闭症和精神发育迟滞的神经行为异常中的确切作用仍有待确定。我们将利用 NL 敲除、人类疾病突变敲除以及后续研究中条件敲除小鼠的电生理和行为特征来确定 Neuroligin 在体内的作用。驱动假设是，缺乏 NL 基因或携带已知与疾病相关的 NL 突变的小鼠将表现出与人类自闭症或智力迟钝一致的行为差异，并且这些行为差异将与体内皮质回路中 E/I 平衡或突触功能的特定异常相关。将解决以下具体目标： 1. 确定 NL3 疾病相关突变或 NL3 缺失是否会导致自闭症和智力低下相关的行为异常。 2. 确定NL3或NL3疾病相关突变的缺失是否会导致兴奋性和抑制性突触连接和功能的改变。 3. 确定NL3或NL3疾病相关突变的缺失是否会改变海马中诱导NMDA受体依赖性突触可塑性的阈值。公共卫生相关性：自闭症谱系障碍和精神发育迟滞是常见的、使人衰弱的疾病，涉及社会互动或认知功能，在一部分患者中具有临床重叠。最近，跨突触细胞粘附分子 Neuroligin 家族成员的功能丧失突变与人类自闭症和智力低下有关。具有 Neuroligin 基因改变的小鼠将被定性为潜在的自闭症和智力迟钝动物模型，以更好地了解这些使人衰弱的疾病的原因和治疗方法。