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Inhibitors of Synaptogenesis and Mental Health

突触发生和心理健康的抑制剂

基本信息

批准号：
10468640
负责人：
Roman Jeno Giger
金额：
$ 49.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468640
关键词：
1q32 Ablation Acoustics Adult Affect Alleles Anatomy Anxiety Attention deficit hyperactivity disorder Behavior Behavioral Binding Binding Proteins Biochemical Pathway Biochemistry Biological Assay Biology Biotin Bipolar Disorder Brain Brain region Chromatin Chromosomes Co-Immunoprecipitations Complement Complex Defect Development Disease Electrophysiology (science)Embryo Ensure Episodic memory Excitatory Synapse Exhibits Family Family member GTPase-Activating Proteins Gene Dosage Gene Expression Gene Family Genes Genetic Genetic Risk Genetic study Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Histologic Human Impairment Knock-out Knockout Mice Knowledge Label Lead Link Magnetic Resonance Imaging Maps Mental Health Mental disorders Methods Monitor Mood Disorders Morphology Mus Mutant Strains Mice Mutation Neurons Neurophysiology - biologic function Neurotic Disorders Pathway interactions Phenotype Physiology Play Point Mutation Predisposition Process Prosencephalon Protein Deficiency Proteins Proteomics Reporting Research Resolution Risk Risk Factors Role Schizophrenia Semaphorins Signal Transduction Startle Reaction Structure Synapses Synaptic Transmission System Techniques Tertiary Protein Structure Testing Transgenic Mice Variant Vertebral column autism spectrum disorder axon guidance axonal pathfinding base behavioral impairment behavioral phenotyping biochemical tools brain morphology cell motility cell type conditional knockout density dentate gyrus experimental study fetal gene function genetic approach genetic variant granule cell inhibitor insight interdisciplinary approach interest member migration mouse genetics mutant neural circuit neurodevelopment neuroepithelium neuropsychiatric disorder neuropsychiatry neuroregulation neurotransmission novel novel therapeutic intervention plexin protein function receptor relating to nervous system sex stem cells symptomatology synaptic function synaptogenesis trait

项目摘要

Mounting evidence suggests that many neuropsychiatric disorders have a developmental origin with a strong genetic underpinning. A large number of allelic variants has been identified that associate with mental illness. While genetic discoveries are a crucial first step, the next major challenge is to define the biochemical pathways altered by disease alleles and to develop a more nuanced understanding of how these dysfunctional pathways disrupt brain function relevant to disease symptomatology. Of interest, mutations in members of the SEMAPHORIN (SEMA) family of axon guidance molecules, and their receptors, the PLEXINS (PLXN) carry varying genetic risks for mental illness. Allelic variants of SEMA5A and its receptor PLXNA2 associated with mood disorders cause reduced gene expression. To explore the underlying biology of how reduced SEMA5A/PLXNA2 expression may contribute to mental illness, we use Plxna2 transgenic mice as an experimental system. Morphological studies with Sema5a and Plxna2 mutant mice identified distinct anatomical phenotypes: defects in migration of early-born dentate granule cells (GCs) progenitors from the primary neuroepithelium to the dentate gyrus (DG) and an increase in spine synapse density in mature GCs in the DG. Adult Plxna2 mice exhibit gene-dosage and sex-specific behavioral defects in episodic memory, sensorimotor gating, and sociability; traits commonly observed in psychiatric disorders including Schizophrenia. For a deeper understanding of how Plxna2 deficiency may contribute to behavioral phenotypes, we used gene editing to disrupt the GTPase-activating protein (GAP) domain in the PlxnA2 cytoplasmic region. Loss of PlxnA2-GAP enzymatic activity impairs Rap1-GTPase dependent GC progenitor migration and leads to supernumerary spine synapses in mature GC. Moreover, PlxnA2-GAP deficiency disrupts episodic memory and sensorimotor gating. To probe deeper into how impaired Sema5A/PlxnA2-GAP/Rap1 signaling leads to behavioral defects, we used a proteomics-based approach and identified novel PlxnA2 interacting proteins. In the current application we propose a multidisciplinary approach comprised of recently developed biochemical tools, electrophysiological techniques, conditional gene ablation and mouse behavior. SPECIFIC AIM 1 is aimed at the characterization of novel mechanisms that regulate Sema5A-PlxnA2 signaling, including the guanine nucleotide exchange factors (GEFs) that antagonize PlxnA2-GAP activity. SPECIFIC AIM 2 builds on our observation that forebrain specific ablation of Plxna2 mimics behavioral defects observed in Plxna2 germline null mice. We pursue a mouse genetic approach to identify developmental epochs of vulnerability and the neural substrate associated with impaired behaviors in Plxna2-/- and Plxna2-GAP deficient mice. Genetic studies will be complemented by electrophysiological recordings, histological analyses and high- resolution magnetic resonance imaging. Studies are aimed at determining where and when Plxna2-GAP function is required during brain development to ensure normal behavior in adulthood.

越来越多的证据表明，许多神经精神疾病有一个发育的起源与强烈的