The role of Syngap1 in striatal physiology and behavior

Syngap1 在纹状体生理学和行为中的作用

基本信息

批准号：
10042425
负责人：
Helen S. Bateup
金额：
$ 43.18万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-06 至 2023-05-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042425
关键词：
3-Dimensional Acute Affect Area Behavior Behavioral Brain Cellular Morphology Cognitive Cognitive deficits Communication Confocal Microscopy Corpus striatum structure Dendritic Spines Developmental Delay Disorders Disease Electrophysiology (science)Epilepsy Event Excitatory Synapse Exhibits Foundations Functional disorder Genes Genetic Growth Habits Hippocampus (Brain)Intellectual functioning disability Knockout Mice Label Language Delays Learning Link Long-Term Potentiation Measures Mediating Messenger RNA Modeling Monomeric GTP-Binding Proteins Morphology Motor Movement Mus Mutation N-Methyl-D-Aspartate Receptors Neurodevelopmental Disorder Neurons Obsessive compulsive behavior Output Pathology Pathway interactions Patients Pattern Physiological Physiology Play Positioning Attribute Problem behavior Property Proteins Receptor Signaling Regulation Research Resolution Role Sensory Signal Transduction Slice Structure Suggestion Symptoms Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing Therapeutic Vertebral column Work autism spectrum disorder behavioral phenotyping brain cell calmodulin-dependent protein kinase II cell type conditional knockout de novo mutation density experimental study flexibility genetic approach habit learning imaging approach improved motor behavior motor deficit motor learning novel optogenetics prevent reconstruction response restoration risk variant stereotypy synaptic function trafficking transmission process

项目摘要

PROJECT SUMMARY SYNGAP1-related non-syndromic intellectual disability is a neurodevelopmental disorder caused by mutations in the SYNGAP1 gene. SYNGAP1 encodes the protein SynGAP, which is a highly abundant protein in the post-synaptic density of excitatory synapses. At synapses, SynGAP functions to repress downstream NMDAR signaling and AMPAR trafficking through its inhibition of small GTPases. Translocation of SynGAP out of the post-synaptic density is required to allow NMDAR-dependent long- term potentiation (LTP). In the absence of SynGAP, NMDAR-dependent plasticity is unrestrained leading to alterations in synapse strength, spine structure, and plasticity. While the functions of SynGAP have been nearly exclusively studied in the cortex and hippocampus, the striatum also exhibits high levels of SynGAP expression. Striatal projection neurons are GABA-ergic neurons covered in a dense array of dendritic spines that receive excitatory input from multiple cortical areas. SynGAP is therefore positioned to play a key role in gating synaptic transmission and plasticity at corticostriatal synapses. Despite this, SynGAP’s functions in striatal synaptic physiology have not yet been defined. Moreover, several of the major symptoms of SYNGAP1 disorder likely involve striatal pathophysiology including autism spectrum disorder, obsessive-compulsive behavior, motor developmental delay, hyperexcitability, and other behavioral problems. In this exploratory study, we will elucidate the consequences of SynGAP loss on striatal synaptic function and determine whether loss of SynGAP from striatal neurons is sufficient to induce behavioral alterations relevant for SYNGAP1 disorder. Specifically, in Aim 1 we will determine how loss of SynGAP impacts corticostriatal synaptic transmission and plasticity. In addition, we will use advanced imaging approaches to investigate how SynGAP deficiency affects dendritic spine number and morphology. In Aim 2, we will determine whether deletion of Syngap1 from specific striatal cell types is sufficient to alter motor behaviors, habit learning, and cognitive flexibility. We will further test whether restoration of SynGAP expression only in striatal projection neurons is capable of preventing behavioral abnormalities using a genetic rescue strategy. Together, this work will provide an essential starting point for understanding SynGAP’s functions at striatal synapses and identify the striatal cell type(s) most relevant for the manifestations of SYNGAP1-related disorders.

项目摘要与SynGAP1相关的非混合智力障碍是神经发育障碍由Syngap1基因中的突变引起。 Syngap1编码蛋白质杂质，这是一个高度兴奋性突触的突触后密度中最富有的蛋白质。在突触时，Syngap功能通过抑制小型GTP酶的抑制NMDAR信号传导和AMPAR运输。 Syngap从突触后密度中易位以允许NMDAR依赖性长术语增强（LTP）。在没有Syngap的情况下，NMDAR依赖性可塑性不受约束导致突触强度，脊柱结构和可塑性改变。而功能 Syngap几乎仅在皮质和海马中仅研究了，纹状体也是表现出高水平的合成表达。纹状体投影神经元是GABA - 凝神经元覆盖着来自多个皮质区域的兴奋性输入的一系列密集的树突状刺。因此，Syngap的定位是在门控突触传播和可塑性中发挥关键作用皮质纹状体突触。尽管如此，Syngap在纹状体突触生理中的功能尚未被定义。此外，Syngap1疾病的一些主要症状可能涉及纹状体病理生理学包括自闭症谱系障碍，强迫症，运动发育延迟，过度兴奋和其他行为问题。在这项探索性研究中，我们将阐明合成损失对纹状体突触功能的后果，并确定是否丢失来自纹状体神经元的合成性足以诱导与Syngap1相关的行为改变障碍。特别是，在目标1中，我们将确定syngap损失如何影响皮质纹状体突触传输和可塑性。此外，我们将使用高级成像方法来研究 Syngap缺乏会影响树突状的脊柱数和形态。在AIM 2中，我们将确定从特定纹状体细胞类型中删除Syngap1是否足以改变运动行为，习惯学习和认知灵活性。我们将进一步测试是否仅在纹状体投影神经元能够使用遗传救援预防行为异常战略。这项工作将为理解Syngap的工作提供一个重要的起点纹状体突触的功能并确定与表现最相关的纹状体细胞类型与SynGAP1相关的疾病。