The role of Syngap1 in striatal physiology and behavior

Syngap1 在纹状体生理学和行为中的作用

• 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
• 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

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 SYNGAP 1相关的非综合征性智力残疾是一种神经发育障碍 是由SYNGAP 1基因突变引起的。SYNGAP 1编码蛋白质SynGAP，这是一种高度保守的蛋白质。 在兴奋性突触的突触后密度中有丰富的蛋白质。在突触处，SynGAP的功能是 通过抑制小GTP酶抑制下游NMDAR信号传导和AMPAR运输。 需要SynGAP易位出突触后致密物，以允许NMDAR依赖性长-短链突触。 术语增强（LTP）。在缺乏SynGAP的情况下，NMDAR依赖性可塑性不受限制 导致突触强度、棘结构和可塑性的改变。虽然功能 SynGAP几乎只在皮层和海马中进行了研究，纹状体也是如此。 表现出高水平的SynGAP表达。纹状体投射神经元是GABA能神经元 覆盖着密集的树突棘，接受来自多个皮层区域的兴奋性输入。 因此，SynGAP定位为在门控突触传递和可塑性方面发挥关键作用， 皮质纹状体突触尽管如此，SynGAP在纹状体突触生理学中的功能还没有被证实。 被定义。此外，SYNGAP 1紊乱的几个主要症状可能涉及纹状体的 病理生理学，包括自闭症谱系障碍、强迫行为、运动 发育迟缓、过度兴奋和其他行为问题。在这项研究中，我们将 阐明SynGAP缺失对纹状体突触功能的影响，并确定SynGAP缺失是否 来自纹状体神经元的SynGAP足以诱导与SYNGAP 1相关的行为改变 disorder.具体来说，在目标1中，我们将确定SynGAP的缺失如何影响皮质纹状体突触。 传输和可塑性。此外，我们将使用先进的成像方法来研究如何 SynGAP缺陷影响树突棘的数量和形态。在目标2中，我们将确定 特定纹状体细胞类型中Syngap 1的缺失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细胞中恢复SynGAP表达， 纹状体投射神经元能够利用遗传拯救来防止行为异常 战略总之，这项工作将为理解SynGAP的 功能，并确定纹状体细胞类型最相关的表现， SYNGAP 1相关疾病。