Role of CREST in Cortical Development and Plasticity

描述(申请人提供)：感官体验通过激活神经回路影响大脑发育。这些通路的激活导致神经元功能的各个方面的钙依赖调节，如突触可塑性、细胞存活、轴突和树突重塑。在大多数情况下，钙信号通过激活诱导目标基因表达的转录因子来发挥长期的细胞效应。我们的总体目标是深入了解钙信号通过转录激活影响大脑发育的机制。钙信号在神经元中的主要作用之一是调节突触强度的变化。在许多突触，突触强度变化的方向和程度取决于刺激参数。例如，在海马区的CA3-CA1侧支突触，低频刺激导致长期抑制(LTD)，高频刺激导致长期增强(LTP)。突触经历可塑性的能力本身可以通过各种操作来改变，由此导致的细胞可塑性状态的变化通常被称为化塑性。我们建议探索CA3-CA1突触的化塑性受CREST介导的转录调控的假说。该项目的目标是：(I)研究CREST在活性依赖性下调GluR2表达中的作用；(Ii)研究CREST在活性依赖性调控NR2B表达中的作用；(Iii)研究CREST在体内调节AMPA/NMDA比率中的作用，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CREST的缺失是否影响变塑性。与公共健康相关：该项目的目标是了解一种名为CREST的核因子在海马区连接的发展和重组中的作用。一些发育性神经疾病，如自闭症和Rett综合征，其特点是神经元连接缺陷，但这些疾病的细胞和分子基础尚不清楚。我们最近发现，CREST调节几个基因的表达，包括在Rett综合征中突变的MeCP2基因。我们将研究CREST如何调节MeCP2的表达，以及这如何影响大脑对突触输入的反应能力。该项目的研究结果将指导人们更好地理解和制定儿童神经性疾病的治疗策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand the role of a nuclear factor called CREST in the development and reorganization of hippocampal connections. Several developmental neurological disorders, such as Autism and Rett syndrome, are characterized by defects in neuronal connectivity, but the cellular and molecular basis of these disorders is not well-understood. We have recently found that CREST regulates the expression of several genes, including MeCP2, a gene that is mutated in Rett Syndrome. We will examine how CREST regulates MeCP2 expression and how that affects the ability of the brain to respond to synaptic inputs. The findings of this project should guide efforts to better understand and develop therapeutic strategies for childhood neurological disorders.