Molecular pathways connecting NMDA receptors to the actin cytoskeleton

点击翻译按钮获取中文摘要

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.