Role of CREST in Cortical Development and Plasticity

项目摘要 感觉体验通过激活神经回路来影响大脑发育。这个 这些通路的激活导致钙依赖的调控的各个方面 神经元功能，如突触可塑性、细胞存活、轴突和树突 改建。在大多数情况下，钙信号会对细胞产生持久的影响 通过激活转录因子来诱导目标基因的表达。我们的整体 目标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 突触的力量。在许多突触，突触变化的方向和程度 强度取决于刺激参数。例如，在CA3-CA1谢弗 海马区的侧支突触，低频率刺激导致长时间 抑制(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不同的方式来改变 操作，以及由此导致的细胞可塑性状态的转变通常被称为 作为超塑性。我们建议探索一种假设，即在CA3- CA1突触受CREST介导的转录调控。该项目的目标 是：(I)研究CREST在活性依赖的GluR2下调中的作用 (Ii)研究CREST在NR2B活性依赖调控中的作用 表达；(Iii)研究CREST在调节AMPA/NMDA比例中的作用 并确定CREST是否调节沉默突触的部分；以及(Iv) 确定CREST是否调节海马CA3-CA1突触中的LTP以及是否丢失 冠状突起损害了可塑性。

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.