Molecular pathways connecting NMDA receptors to the actin cytoskeleton

NMDAR是一种谷氨酸神经递质受体，广泛表达于中枢神经系统。它们在突触可塑性过程中起着重要作用。突触可塑性是指神经元改变发育中的大脑和整个生命过程中连接的强度和数量的过程。 NMDAR是许多形式的突触可塑性所必需的，当NMDAR功能受损时，它会影响发育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的可塑性伴随着树突棘的数量和形态的变化。因此，NMDAR功能障碍会导致树突棘的丢失，尽管导致这种情况的分子事件尚未确定。 在我们的实验室中，我们使用药理学和遗传学的小鼠模型研究了NMDAR功能障碍的影响。NMDAR基因敲除小鼠的皮质和纹状体脊椎密度降低，在几项认知任务中学习和记忆受损。我们已经开始阐明当NMDARs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。已知这一途径调节肌动蛋白细胞骨架的动力学，而Rho信号的变化会导致脊柱数量和形态的变化。因此，我们假设NMDAR功能障碍对RhoGTPase信号的影响是脊柱丢失的原因。 这项建议的总体目标是阐明将NMDAR活性与肌动蛋白细胞骨架联系起来控制脊柱形状和数量的分子机制。在第一个目标中，我们将确定RhoGTPase通路的哪些组成部分受到NMDARs的遗传或药物操作的影响。这项工作将在原代神经元培养和体内进行。在这项提案的第二个目标中，我们将操纵RhoGTPase效应器的水平和活性，以确定这是否可以逆转由NMDAR功能障碍引起的脊柱缺陷和认知障碍。 拟议的研究是我们实验室正在进行的研究计划的重要组成部分，该计划旨在了解NMDA受体调节基因表达和神经细胞生物学的许多方式。我们想了解特定类型的细胞在NMDA受体触发的信号转导级联中有何不同，以及这最终是如何影响突触功能的。

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.