Role of CREST in Cortical Development and Plasticity

项目摘要 感官体验通过激活神经回路影响大脑发育。的 这些途径的激活导致钙依赖性调节的各个方面， 神经元功能如突触可塑性、细胞存活以及轴突和树突 重塑在大多数情况下，钙信号发挥长期的细胞效应 通过激活诱导靶基因表达的转录因子。我们的整体 目的是深入了解钙信号影响大脑的机制 通过转录激活来发育。 钙信号在神经元中的主要作用之一是调节神经元内钙离子浓度的变化。 突触强度在许多突触中，突触的变化方向和程度 强度取决于刺激参数。例如，在CA 3-CA 1 Schaffer 在海马体中的侧支突触，低频刺激导致长时间的 抑郁症（LTD）和高频刺激导致长时程增强（LTP）。 突触经历可塑性的能力本身可以通过各种方式进行修改。 操纵，以及由此产生的细胞可塑性状态的转变通常被称为 作为亚塑性。我们建议探讨这一假设，即在CA 3- CA 1突触受CREST介导的转录调控。该项目的目标 （i）研究CREST在GluR 2活性依赖性下调中的作用 （ii）研究CREST在NR 2B活性依赖性调节中的作用。 （iii）研究CREST在调节AMPA：NMDA比率中的作用， 体内并确定CREST是否调节沉默突触的分数;以及（iv） 确定CREST是否调节海马CA 3-CA 1突触中的LTP以及是否丢失 的CREST妥协亚塑性。

Project Summary Sensory experience influences brain development by activating neural circuits. The activation of these pathways leads to calcium-dependent regulation of various aspects of neuronal function such as synaptic plasticity, cell survival, and axonal and dendritic remodeling. In most of these instances calcium signals exert long-lasting cellular effects by activating transcription factors that induce expression of target genes. Our overall goal is to gain insight into the mechanisms by which calcium signals influence brain development via transcriptional activation. One of the major effects of calcium signaling in neurons is to regulate changes in synaptic strength. At many synapses, the direction and extent of change in synaptic strength depends on the stimulus parameters. For example, at the CA3-CA1 Schaffer collateral synapse in the hippocampus, low frequency stimulation leads to long term depression (LTD) and high frequency stimulation leads to long term potentiation (LTP). The ability of a synapse to undergo plasticity can itself be modified by various manipulations, and the resulting shift in the plasticity state of the cell is often referred to as metaplasticity. We propose to explore the hypothesis that metaplasticity at the CA3- CA1 synapse is regulated by CREST-mediated transcription. The goals of the project are: (i) To examine the role of CREST in activity-dependent down-regulation of GluR2 expression; (ii) To examine the role CREST in activity-dependent regulation of NR2B expression; (iii) To examine the role of CREST in regulating the AMPA: NMDA ratio in vivo and to determine if CREST regulates the fraction of silent synapses; and (iv) To determine if CREST regulates LTP in hippocampal CA3-CA1 synapses and whether loss of CREST compromises metaplasticity.