Synaptic Analysis of Neuroligin1 function

Neuroligin1 功能的突触分析

• 批准号: 7676907
• 负责人: Marc V Fuccillo
• 金额: $ 5.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676907
• 关键词: Acute; Address; Binding; Biochemical; Biological Assay; Biological Models; Biological Process; Brain; Cells; Disease; Excitatory Postsynaptic Potentials; Excitatory Synapse; Future; Genes; Genetic; Goals; Hippocampus (Brain); In Vitro; Individual; Injection of therapeutic agent; Intervention; Kinetics; Knockout Mice; Knowledge; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Mediator of activation protein; Mental disorders; Molecular; Molecular Biology; Mus; Mutation; Neurons; Output; Physiologic pulse; Physiology; Point Mutation; Preparation; Probability; Proteins; Protocols documentation; Pyramidal Cells; Role; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Whole-Cell Recordings; Work; autism spectrum disorder; developmental disease; extracellular; ifenprodil; in vivo; loss of function; mutant; neuropsychiatry; postnatal; postsynaptic; research study; synaptic function; transmission process; voltage

DESCRIPTION (provided by candidate): The overarching goal of this proposal is to explore the mature synaptic function of Neuroliginl, a synapse- specific protein implicated in several autism spectrum disorders (ASDs). Molecular biology and mouse genetics will be used together with synaptic physiology to better understand the normal biological function of NL1 and the possible contributions of mutations in this gene to abnormal synaptic function in neuropsychiatric disorders. In addition to providing potential model systems for the study of ASDs, results from this work will contribute significantly to the limited understanding of NL function at mature synapses. In doing so, they may provide new targets for future molecular interventions in psychiatric disorders. Previous work from the hippocampus of NL1 knockout mice demonstrated a 50% reduction in the NMDAR/AMPAR ratio at Schaffer collateral/CA1 synapses. My first two specific aims will specifically address this observation by separately characterizing alterations in AMPAR- and NMDAR-mediated currents in control and NL1 mutant acute hippocampal slice preparations. I will follow these experiments by testing whether NL1 functions in NMDAR-dependent long-term potentiation (LTP) or long-term depression (LTD) at Schaffer collateral-CA1 synapses. Finally, to assess whether NL1 control of synaptic transmission has a pre- or post- synaptic locus, I will use postnatal lentiviral injection in vivo to "rescue" individual cells in NL1 KO mice with point mutants that disrupt either extracellular (3-neurexin binding or intracellular binding to PSD-95. The results of these experiments should both compliment our current in vitro knowledge while enhancing our understanding of the function of NL1 in the mature hippocampal circuit. Autism spectrum disorders (ASDs) comprise a heterogeneous group of neuro-developmental disorders that are highly heritable. Neuroliginl, a molecule found at synapses, has been implicated in familial ASDs. This proposal seeks to better understand the function of NL1 in the mature brain so that disorders resulting from abnormalities in this gene can one day be ameliorated.

描述（由候选人提供）：该提案的总体目标是探索神经素的成熟突触功能，神经素（一种突触特异性蛋白质，与几种自闭症谱系障碍（ASDS）有关。分子生物学和小鼠遗传学将与突触生理一起使用，以更好地了解NL1的正常生物学功能以及该基因中突变对神经精神疾病中突触异常的功能的可能贡献。除了为ASD的研究提供潜在的模型系统外，这项工作的结果还将显着有助于对成熟突触中NL功能的有限理解。这样一来，它们可能会为未来的精神疾病分子干预提供新的目标。 NL1基因敲除小鼠海马的先前工作表明，在Schaffer Colternal/Ca1突触时，NMDAR/AMPAR比率降低了50％。我的前两个具体目标将通过分别表征对照中AMPAR和NMDAR介导的电流的变化以及NL1突变体急性海马切片制剂来特别解决这一观察结果。我将通过测试Schaffer Collat​​eral-CA1突触中的NMDAR依赖性长期增强（LTP）或长期抑郁症（LTD）中的NL1功能是通过测试NL1的功能。最后，为了评估NL1对突触传播的控制是否具有突触前或突触后的基因座，我将使用出生后的慢病毒注射体内在NL1 KO小鼠中“挽救”具有点突变体的NL1 KO小鼠中的单个细胞，这些突变体会破坏细胞外的细胞外（3- neurexnolulular）（3-系数的结合或对PSD-95的实验，我们都会在这些实验中造成这些实验。 NL1在成熟的海马电路中的功能。基因有一天可以改善。