Investigating Syngap1 as a regulator of striatal synaptic function

研究 Syngap1 作为纹状体突触功能的调节因子

基本信息

批准号：
10512334
负责人：
Helen S. Bateup
金额：
$ 38.9万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512334
关键词：
3-Dimensional AMPA Receptors Acute Adult Affect Behavior Behavior Control Behavioral Brain CRISPR-mediated transcriptional activation Cellular Morphology Communication Corpus striatum structure Dendritic Spines Development Developmental Delay Disorders Disease Electrophysiology (science)Epilepsy Excitatory Synapse Exhibits Foundations Functional disorder Genes Genetic Hippocampus (Brain)Intellectual functioning disability Knockout Mice Label Language Delays Learning Link Long-Term Potentiation Measures Microscopy Modeling Monomeric GTP-Binding Proteins Morphology Motor Motor Skills Movement Mus Mutation N-Methyl-D-Aspartate Receptors Neurodevelopmental Disorder Neurons Output Pathway interactions Patients Pattern Phenotype Physiology Play Positioning Attribute Problem behavior Property Proteins Receptor Signaling Regulation Research Resolution SYNGAP1 Sensory Signal Transduction Slice Structure Suggestion Symptoms Synapses Synaptic Transmission Syndrome Testing Thalamic structure Therapeutic Therapeutic Intervention Vertebral column Work autism spectrum disorder behavioral phenotyping brain cell cell type conditional knockout critical period de novo mutation density experimental study flexibility habit learning imaging approach improved motor control motor disorder motor impairment mouse model optogenetics postnatal development reconstruction response restoration risk variant selective expression stereotypy synaptic function trafficking transmission process

项目摘要

PROJECT SUMMARY SYNGAP1-related intellectual disability is a neurodevelopmental disorder caused by mutations in the SYNGAP1 gene. SYNGAP1 encodes 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 cultured neurons. 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 well- 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, which receive excitatory inputs from the cortex. SynGAP is therefore positioned to play a key role in gating transmission and plasticity at striatal synapses. Despite this, SynGAP’s functions in striatal neurons have not yet been defined. Importantly, several of the major symptoms of SYNGAP1 disorder are likely to involve alterations in striatal activity including motor developmental delay, repetitive and restrictive behaviors, and other behavioral problems. In this project, 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, we will determine how loss of SynGAP impacts striatal synaptic development, transmission and plasticity. In addition, we will use imaging approaches to investigate how SynGAP deficiency affects spinogenesis, spine number and morphology. To determine whether deletion of Syngap1 from striatal neurons is sufficient to alter disease-relevant behaviors, we will investigate how haploinsufficiency of Syngap1 in cell type-specific knock-out mice affects motor function, habit learning, and behavioral flexibility. Finally, we will test whether restoration of Syngap1 expression selectively in striatal projection neurons can improve synaptic and behavioral abnormalities using genetic rescue strategies. Together, this work will 1) further our understanding of SynGAP’s functions at striatal synapses, 2) identify the striatal cell type(s) most relevant for the manifestations of SYNGAP1 disorder, and 3) define critical periods for the onset and rescue of disease-related phenotypes.

项目摘要与SynGAP1相关的智障是由突变引起的神经发育障碍 Syngap1基因。 Syngap1编码syngap，这是后期高度丰富的蛋白质兴奋性突触的突触密度。在突触中，Syngap功能以压制下游NMDAR 信号传导和AMPAR运输通过抑制小GTP酶。 syngap易位需要后突触密度以允许培养的NMDAR依赖性长期增强（LTP）神经元。在没有Syngap的情况下，NMDAR依赖性可塑性是不受约束的，导致改变在突触强度，脊柱结构和可塑性中。虽然syngap的功能已经很好纹状体在皮质和海马中研究，还表现出高水平的syngap表达。纹状体投射神经元是覆盖着密集的树突状刺的GABA - 凝胶神经元，它们从皮层接收兴奋性输入。因此，Syngap可以在门控中发挥关键作用纹状体突触时的传递和可塑性。尽管如此，Syngap在纹状体神经元中的功能具有尚未定义。重要的是，Syngap1疾病的几种主要症状很可能涉及纹状体活动的改变，包括运动发育延迟，重复性和限制性行为和其他行为问题。在这个项目中，我们将阐明syngap损失对纹状体突触功能的后果并确定纹状体神经元中的syngap是否足以诱导行为改变与Syngap1疾病有关。具体而言，我们将确定syngap损失如何影响纹状体突触发育，传播和可塑性。此外，我们将使用成像方法研究合成缺乏如何影响旋转生成，脊柱数和形态。确定从纹状体神经元中缺失Syngap1是否足以改变与疾病相关的行为，我们将研究细胞类型特异性敲除小鼠中Syngap1的单倍不足如何影响运动功能，习惯学习和行为灵活性。最后，我们将测试Syngap1表达的恢复有选择地在纹状体投影神经元中可以使用遗传来改善突触和行为异常救援策略。这项工作将共同1）进一步了解Syngap在纹状体上的功能突触，2）确定与Syngap1疾病表现最相关的纹状体细胞类型， 3）定义了与疾病相关表型发作和营救的关键时期。