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Integrin-Arg-SHP2 signaling regulates NMDAR function and neuron morphology

整合素-Arg-SHP2信号调节NMDAR功能和神经元形态

基本信息

批准号：
9128713
负责人：
Aaron Donald Levy
金额：
$ 2.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128713
关键词：
Address Adolescence Affect Alleles Alzheimer&apos s Disease Attenuated Autistic Disorder Binding Biochemical Biotinylation Cognitive deficits Confocal Microscopy Data Defect Dendrites Dendritic Spines Diagnosis Disease Economic Burden Electron Microscopy Electrophysiology (science)Functional disorder Genetic Head Health Hippocampus (Brain)Integrin alpha3beta1 Integrins Knock-in Link Maintenance Measures Mediating Mental Retardation Mental disorders Molecular Mood Disorders Morphology Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Neurodegenerative Disorders Neurons Noonan Syndrome PTPN11 gene Pathology Phosphorylation Phosphorylation Site Play Prosencephalon Protein Tyrosine Kinase Regulation Regulatory Pathway Role Schizophrenia Signal Transduction Site Slice Structure Surface Synapses Techniques Testing Therapeutic Intervention Tyrosine Phosphorylation Site Vertebral column addiction adhesion receptor autism spectrum disorder density developmental disease excitatory neuron gain of function insight mutant nervous system disorder neuron loss receptor function research study social treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Integrin-Arg-SHP2 signaling regulates NMDAR function and neuron morphology. Dendritic spine stability is disrupted in psychiatric and neurological disorders. Regulation of NMDA receptor (NMDAR) activity by integrin adhesion receptors plays a fundamental role in dendritic spine maturation and stability, but the molecular mechanisms by which integrins regulate NMDARs are unknown. We have shown that loss of integrin α3ß1 signaling through the Abl2/Arg non-receptor tyrosine kinase causes widespread dendritic spine loss in late adolescence due to increased GluN2B subunit-mediated NMDA receptor currents. I provide strong evidence that Arg acts through the tyrosine phosphatase SHP2 to control GluN2B phosphorylation and function. NMDA receptor dysfunction is a hallmark of psychiatric, neurodevelopmental and neurological diseases such as schizophrenia, autism, and Alzheimer's disease. Understanding the mechanism by which integrins regulate NMDAR function is critical to understand how synaptic stability is compromised in these disorders and to develop treatment strategies. In this proposal, I will test the hypothesis that integrin-Arg-SHP2 signaling functionally regulates the NMDA receptor to control dendritic spine stability. My first aim is to determine how SHP2 regulates GluN2B phosphorylation and function. In this aim, I will use substrate-trapping mutants of SHP2 to test whether GluN2B is directly dephosphorylated by SHP2 and to determine which site in GluN2B is targeted by SHP2. GluN2B phosphorylation promotes its surface localization. Therefore, I will also use surface biotinylation of NMDARs in cultured hippocampal neurons to measure how genetic and pharmacological loss- or gain-of-function of Arg and SHP2 influence NMDAR surface expression. My second aim is to elucidate an integrin-NMDA receptor regulatory mechanism. GluN2B phosphorylation increases NMDAR-mediated currents, and my preliminary data show that activation of SHP2 decreases GluN2B phosphorylation. To test how SHP2 regulates NMDAR function, I will measure how loss- or gain-of-function of SHP2 activity affects NMDAR-mediated currents in hippocampal slices. I will also test the hypothesis that SHP2 functions as a mechanistic link between integrin-Arg signaling and the NMDAR by assessing whether an SHP2 gain-of-function allele can suppress elevated NMDAR currents in mice lacking integrin α3ß1 or Arg. My third aim is to understand how SHP2 regulates dendritic spine and synapse structure. Our lab has shown that integrin-Arg signaling attenuates NMDAR activity to stabilize spines, and I hypothesize that SHP2 mediates the effects of Arg signaling on NMDAR function. I will use confocal and electron microscopy to quantitatively measure how loss- and gain-of-function of SHP2 activity in mice affects dendritic spine and synapse structure and stability. I will also test whether an activated SHP2 allele can suppress the spine destabilization resulting from loss of integrin α3ß1 or Arg in mice.