The role of Syngap1 in striatal physiology and behavior

项目总结 Syngap1相关的非综合征性智能障碍是一种神经发育障碍 由SYNGAP1基因突变引起。Syngap1编码SynGAP蛋白，它是一种高度 兴奋性突触的突触后密度中蛋白质丰富。在突触，SynGAP的功能是 通过抑制小的GTP酶，抑制下游的NMDAR信号和AMPAR的运输。 需要将SynGAP移位到突触后密度之外，以允许NMDAR依赖的长时间- 术语增强(LTP)。在没有SynGAP的情况下，NMDAR依赖的可塑性是不受限制的 导致突触强度、脊柱结构和可塑性的改变。虽然它的功能是 SynGAP几乎只在皮质和海马区进行研究，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阵列，接受来自多个皮质区域的兴奋性输入。 因此，SynGAP在门控突触传递和可塑性方面发挥关键作用 尽管如此，SynGAP在纹状体突触生理学中的功能尚未 已经被定义了。此外，SYNGAP1障碍的几个主要症状可能与纹状体有关 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。在这项探索性研究中，我们将 阐明SynGAP缺失对纹状体突触功能的影响，并确定 纹状体神经元的SynGAP足以诱导与SYNGAP1相关的行为改变 无序。具体地说，在目标1中，我们将确定SynGAP的丢失如何影响皮质纹状体突触 传递性和可塑性。此外，我们将使用先进的成像方法来研究 SynGAP缺乏会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的Syngap1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SynGAP的表达是否仅在 纹状体投射神经元能够通过基因拯救来防止行为异常 策略。总之，这项工作将为理解SynGAP的 纹状体突触的功能和识别与纹状体细胞类型最相关的纹状体细胞类型(S) Syngap1相关疾病。

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.