GluN2D in Development and Disease

项目摘要/摘要 NMDA受体(NMDAR)是由谷氨酸激活的配体门控离子通道。 大脑的主要兴奋性神经递质。NMDAR亚基的错义突变是 与多种神经发育障碍有关，包括自闭症、癫痫和 形态异常。然而，目前还不清楚具体的功能改变是如何 产生疾病的，尤其是当功能等位基因的获得和丧失都已被确认为 同样的障碍。这项建议以斑马鱼为模型来探索发育的作用。 研究不足的GluN2D亚基，它与一种严重的神经疾病有关， 发育性和癫痫性脑病(DeE)。基于新的初步数据， 显示NMDAR抑制前脑神经发生，我们假设GluN2D功能障碍 改变早期神经发生和随后兴奋性和抑制性神经元的平衡。我们 提出两个目的来检验这一前提。在目标1中，我们将确定完全丧失 GluN2D对神经发生的影响为了解其致病作用奠定基础 GluN2D疾病变异体。在目标2中，我们将生成与DIE相关的斑马鱼模型 GluN2D变种，以直接评估其对神经发生的影响。这项工作将提供新的 洞察GluN2D在早期开发中的作用，并建立可扩展的战略以 询问与疾病相关的NMDAR变体的致病机制 导致自闭症、癫痫和其他神经发育障碍。

PROJECT SUMMARY/ABSTRACT NMDA receptors (NMDARs) are ligand-gated ion channels that are activated by glutamate, the principle excitatory neurotransmitter of the brain. Missense mutations in NMDAR subunits are associated with multiple neurodevelopmental disorders including autism, epilepsy and morphological anomalies. Nevertheless, it is unclear how particular functional alterations produce disease, especially as both gain and loss of function alleles have been identified with the same disorders. This proposal uses zebrafish as a model to explore the developmental roles of the understudied GluN2D subunit, which is associated with a severe neurological disorder, Developmental and Epileptic Encephalopathy (DEE). Based on novel preliminary data that shows NMDARs repress forebrain neurogenesis, we hypothesize that GluN2D dysfunction alters early neurogenesis and the subsequent balance of excitatory and inhibitory neurons. We propose two aims to test this premise. In Aim 1 we will determine the effects of complete loss of GluN2D on neurogenesis to establish a foundation for understanding the pathogenic impacts of GluN2D disease variants. In Aim 2 we will generate zebrafish models harboring DEE-associated GluN2D variants to directly assess their effects on neurogenesis. This work will provide new insights into the role of GluN2D in early development and establish a scalable strategy to interrogate the pathogenic mechanisms produced disease associated NMDAR variants that result in autism, epilepsy, and other neurodevelopmental disorders.