Impact of SynGAP1 Mutations on Synapse Maturation and Cognitive Development

描述(申请人提供)：突触功能障碍正在成为神经发育障碍的主要原因，许多编码突触蛋白的基因在这些患者中发生突变。几种影响树突棘结构和功能的罕见突变最近被证明会导致ID，同时也增加了患ASD或癫痫的风险。虽然环境和常见基因突变的独特组合可能是大多数ID和ASD病例的基础，但罕见致病突变的小鼠模型提供了优秀的实验系统，以寻找这些疾病背后的常见病理生物学。然而，致病突变导致的发育突触功能障碍如何影响电路功能和行为在很大程度上仍不清楚。这在ID和ASD中是一个特别重要的考虑因素，因为这些疾病首先在幼儿中被诊断出来。需要将发育突触功能障碍与网络和行为异常联系起来的研究，以开发新的假说来解释这些疾病的病理神经生物学。这些新的假说将指导未来治疗患者的治疗策略。在这项提案中，我们的目标是了解树突突触如何受到ID和ASD所涉及的突变的影响。我们将在一种新兴的ID小鼠模型中进行研究，该模型为我们提供了实验灵活性，以测试新生儿发育过程中树突棘突触的异常成熟正在驱动电路水平的异常，从而阻止正常认知和行为的出现。具体地说，我们认为SYNGAP1基因的单倍体不足，最近被证明导致一种形式的散发性ID，诱导树突棘突触在出生后小鼠大脑发育时期的早期成熟。这些兴奋性突触的早期成熟预计会直接破坏新生神经网络中的E/I平衡，从而影响关键的神经发育里程碑，如可塑性关键期窗口的打开和额外皮质脊椎的修剪。我们的假设预测，这些类型的发育障碍阻止认知和行为技能的获得，这可以解释ID患者这些异常的早期发病和持续性。因此，该项目旨在通过将破坏树突棘成熟的基因突变与影响认知和行为模式成熟的系统水平过程联系起来，更好地了解ID/ASD的病理生物学。预计从这些研究中获得的知识将有助于新的治疗策略，以改善ID患者的生活。

DESCRIPTION (provided by applicant): Synapse dysfunction is emerging as a leading cause of neurodevelopmental disorders and many genes that encode for synapse proteins are mutated in these patients. Several rare mutations that affect dendritic spine structure and function have recently been shown to cause ID, while also increasing the risk for developing ASD or epilepsy. While unique combinations of environment and common genetic mutations likely underlie most cases of ID and ASD, mouse models of rare pathogenic mutations offer excellent experimental systems to search for a common pathobiology underlying these disorders. However, it remains largely unknown how developmental synaptic dysfunction resulting from pathogenic mutations impacts circuit function and behavior. This is a particularly important consideration in ID and ASD because these are disorders first diagnosed in young children. Studies that connect developmental synaptic dysfunction to network and behavioral abnormalities are needed to develop new hypotheses that explain the patho-neurobiology of these disorders. These new hypotheses will guide future therapeutic strategies to treat afflicted patients. In this proposal, we aim to understand how dendritic spine synapses are affected by mutations implicated in ID and ASDs. We will perform studies in an emerging mouse model of ID, which provides us with the experimental flexibility to test the idea that abnormal maturation of dendritic spine synapses in neonatal development are driving circuit-level abnormalities that prevent the emergence of normal cognition and behavior. Specifically, we propose that haploinsufficiency of the SYNGAP1 gene, which has recently been shown to cause a form of sporadic ID, induces an early maturation of dendritic spine synapse in periods of postnatal mouse brain development. The early maturation of these excitatory synapses is expected to directly disrupt E/I balance in nascent neural networks, which then impacts key neurodevelopmental milestones, such as the opening of critical period windows of plasticity and supernumerary cortical spine pruning. Our hypothesis predicts that these types of developmental disruptions prevent the acquisition of cognitive and behavioral skills, which could explain both the early onset and persistent nature of these abnormalities in ID patients. Thus, this project Aims to better understand the pathobiology of ID/ASD by linking genetic mutations that disrupt dendritic spine maturation to systems-level processes known to impact the maturation of cognitive and behavioral modalities. It is expected that knowledge gained from these studies will contribute to novel therapeutic strategies to improve the lives of ID patients.