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，许多神经精神疾病的发育起源很强遗传基础。已经确定了许多与精神疾病相关的等位基因变体。遗传发现是至关重要的第一步，但下一个主要挑战是定义生化疾病等位基因改变的途径，并对这些功能失调的方式产生更细微的理解途径破坏与疾病症状相关的大脑功能。感兴趣的是，成员的突变轴突引导分子的信号素（SEMA）家族及其受体，丛蛋白（PLXN）携带精神疾病的遗传风险有所不同。 Sema5a的等位基因变体及其受体PLXNA2与情绪障碍会导致基因表达降低。探讨如何减少的生物学 SEMA5A/PLXNA2表达可能导致精神疾病，我们使用PLXNA2转基因小鼠作为一种实验系统。 SEMA5A和PLXNA2突变小鼠的形态学研究确定了不同的解剖表型：早期出生的牙齿颗粒细胞（GCS）祖细胞的迁移缺陷对齿状回（DG）的一级神经上皮和成熟GC中脊柱突触密度的增加 DG。成年PLXNA2小鼠在情节记忆中表现出基因剂量和性别特异性行为缺陷，感觉运动门控和社交能力；通常在精神疾病中观察到的特征精神分裂症。为了更深入地了解PLXNA2缺乏症如何促进行为表型，我们使用基因编辑来破坏PLXNA2细胞质区域中GTPase激活蛋白（GAP）结构域。 plxNA2-a-pAP酶活性的丧失会损害RAP1-GTPase依赖GC祖细胞迁移，并导致成熟的GC中的超努脊柱突触。此外，plxna2-gap缺乏破坏了情节记忆和感觉运动门控。更深入地探讨SEMA5A/PLXNA2-GAP/RAP1信号的受损如何导致行为缺陷，我们使用了一种基于蛋白质组学的方法，并鉴定了新型的PLXNA2相互作用蛋白。在我们提出的当前应用程序由最近开发的生化方法组成工具，电生理技术，有条件的基因消融和小鼠行为。具体目标1是针对调节SEMA5A-PLXNA2信号的新机制的表征，包括与PLXNA2-GAP活性拮抗的鸟嘌呤核苷酸交换因子（GEFS）。特定的目标2建立我们的观察到，PLXNA2的前脑特异性消融模仿PLXNA2中观察到的行为缺陷种系无鼠。我们采用鼠标遗传方法来识别脆弱性的发展时期以及与PLXNA2 - / - 和PLXNA2-GAP缺陷小鼠中行为受损相关的神经底物。遗传学研究将由电生理记录，组织学分析和高度互补分辨率磁共振成像。研究旨在确定何时何地plxna2-gap 在大脑发育过程中需要功能以确保成年后正常行为。