Molecular pathways connecting NMDA receptors to the actin cytoskeleton

连接 NMDA 受体与肌动蛋白细胞骨架的分子途径

• 批准号: RGPIN-2018-06409
• 负责人: Ramsey, Amy
• 金额: $ 4.66万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762116
• 关键词: Molecular; pathways; connecting; NMDA; receptors

NMDA receptors (NMDARs) are a type of glutamate neurotransmitter receptor that is widely expressed in the central nervous system. They play a fundamental role in the process of synaptic plasticity. Synaptic plasticity refers to the process by which neurons change the strength and number of connections in the developing brain and throughout life. NMDARs are required for many forms of synaptic plasticity, and when NMDAR function is compromised, it impacts the patterns of connections that are made during development and impairs learning and memory. Interestingly, there is growing evidence that synaptic plasticity is accompanied by changes in the number and morphology of dendritic spines. Accordingly, NMDAR dysfunction leads to a loss of dendritic spines, although the molecular events that cause this have not been determined.In our laboratory, we have studied the impact of NMDAR dysfunction using pharmacological and genetic mouse models. Genetic NMDAR knockdown mice have reductions in cortical and striatal spine density, and have impaired learning and memory in several cognitive tasks. We have begun to elucidate the molecular changes that occur when NMDARs are dysfunctional, and have identified changes in the RhoGTPase signal transduction pathway. This pathway is known to regulate actin cytoskeleton dynamics, and changes in Rho signaling lead to changes in spine number and morphology. Therefore, we hypothesize that the impact of NMDAR dysfunction on RhoGTPase signaling is the cause of spine loss.The overall goal of this proposal is to elucidate the molecular machinery that connects NMDAR activity to the actin cytoskeleton to control spine shape and number. In the first aim, we will determine which components of the RhoGTPase pathways are affected by genetic or pharmacologic manipulation of NMDARs. This work will be performed in primary neuron cultures and in vivo. In the second aim of this proposal, we will manipulate the levels and activity of RhoGTPase effectors to determine whether this reverses spine deficits and cognitive impairments that are caused by NMDAR dysfunction.The proposed studies are a substantial part of our laboratory's ongoing research program, which is to understand the many ways that NMDA receptors regulate gene expression and neuron cell biology. We want to understand how specific cell types differ in the signal transduction cascades that are triggered by NMDA receptors, and how this ultimately affects synaptic function.

NMDA受体（NMDAR）是一种在中枢神经系统中广泛表达的谷氨酸神经递质受体。他们在突触可塑性过程中起着基本作用。突触可塑性是指神经元改变发展大脑和整个生命中连接的强度和数量的过程。许多形式的突触可塑性需要NMDAR，并且当NMDAR功能受到损害时，它会影响开发过程中建立的连接模式，并损害学习和记忆。有趣的是，越来越多的证据表明突触可塑性伴随着树突状刺的数量和形态的变化。因此，NMDAR功能障碍会导致树突状棘的丧失，尽管尚未确定引起这一点的分子事件。在我们的实验室中，我们研究了使用药理学和遗传小鼠模型的NMDAR功能障碍的影响。遗传NMDAR敲低小鼠的皮质和纹状体脊柱密度降低，并且在几种认知任务中的学习和记忆力受损。我们已经开始阐明NMDAR功能失调时发生的分子变化，并确定了Rhogtpase信号转导途径的变化。已知该途径可以调节肌动蛋白细胞骨架动力学，而RHO信号传导的变化会导致脊柱数和形态的变化。因此，我们假设NMDAR功能障碍对RHOGTPase信号的影响是脊柱损失的原因。该提案的总体目标是阐明将NMDAR活性与肌动蛋白细胞骨架连接到脊柱形状和数量的分子机械。在第一个目的中，我们将确定Rhogtpase途径的哪些组成部分受NMDAR的遗传或药理操作的影响。这项工作将在原发性神经元文化和体内进行。 In the second aim of this proposal, we will manipulate the levels and activity of RhoGTPase effectors to determine whether this reverses spine deficits and cognitive impairments that are caused by NMDAR dysfunction.The proposed studies are a substantial part of our laboratory's ongoing research program, which is to understand the many ways that NMDA receptors regulate gene expression and neuron cell biology.我们想了解特定的细胞类型在由NMDA受体触发的信号转导级联反应中如何差异，以及这最终如何影响突触功能。