The CRE/CREB Pathway and Visual Cortical Plasticity

描述(由申请人提供)：发育过程中视觉体验的改变导致初级视觉皮质中连接的戏剧性重组。依赖经验的可塑性能力随着年龄的增长而下降。视觉皮质的可塑性需要cAMP反应元件(cAMP Response Element，CRE)信号通路的激活，这是一个活性依赖的级联反应，导致基因表达。这项建议的目的是更好地确定钙和cAMP依赖的信号成分在视觉皮质可塑性中的参与。我们使用的主要模型是单眼剥夺效应，指的是单眼剥夺引起的视觉皮质功能和形态的变化。我们的假设是，CRE/CREB信号的调节是随着年龄的增长而丧失可塑性的基础，ERK、p90RSK和CREB在可塑性机制中发挥着不同的作用。 具体地说，提出的实验涉及的主要问题是：(1)CREB活动是否调节眼睛优势可塑性的关键期？我们将使用转基因小鼠，转基因小鼠的CREB功能在成人中得到了可调节的增强。(2)p90RSK是否是视皮层活性依赖基因表达的调控开关？我们将表达一种突变形式的RSK2，以检测RSK活性是否控制Cre介导的基因表达和视觉皮质可塑性。(3)Cre/CREB通路的信号成分在视皮层中是如何调节的？我们将使用生化方法来阐明视觉皮质中不同信号成分之间的相互作用。(4)CREB、ERK、p90RSK和Activity如何相互作用来调节视皮层神经元的树突形态？我们将使用表达突变形式的信号分子的病毒系统和GFP一起来评估这些信号蛋白在树突状细胞形态控制中的作用。 我们希望这项研究将阐明发育可塑性的基本机制，以及为什么它会随着年龄的增长而下降。我们的发现可能有助于开发治疗方法，以增强发育和成熟大脑的可塑性，从而有可能治疗中枢视觉功能障碍和其他顽固性大脑疾病。

DESCRIPTION (provided by applicant): Alterations of visual experience in development induce dramatic reorganization of connections in the primary visual cortex. The capacity for experience-dependent plasticity declines with age. Visual cortical plasticity requires the activation of the cAMP responsive element (CRE) signaling pathway, an activity-dependent cascade that leads to gene expression. The objective of this proposal is to better define the involvement of calcium and cAMP-dependent signaling components in visual cortical plasticity. The primary model that we use is the monocular deprivation effect, which refers to changes in visual cortical function and morphology induced by monocular deprivation. Our hypotheses are that regulation of CRE/CREB signaling underlies the loss of plasticity with age and that ERK, p90RSK, and CREB play distinct roles in the plasticity mechanism. Specifically, the major questions addressed by the proposed experiments are: (1) Does CREB activity regulate the critical period for ocular dominance plasticity? We will use transgenic mice engineered to have regulatable enhancement of CREB function in the adult. (2) Is p90RSK the regulatory switch for activity dependent gene expression in the visual cortex? We will express a mutant form of RSK2 to examine whether RSK activity controls CRE-mediated gene expression and visual cortical plasticity. (3) How are signaling components of the CRE/CREB pathway regulated in the visual cortex? We will use biochemical approaches to elucidate the interactions of different signaling components in the visual cortex. (4) How do CREB, ERK, p90RSK, and activity interact to regulate the dendritic morphology of visual cortical neurons? We will use viral system that expresses mutant forms of signaling molecules together with GFP in order to assess the role of these signaling proteins in the control of dendritic morphology. It is our hope that this research will shed light on basic mechanisms underlying developmental plasticity and why it declines with age. Our findings may help in the development of therapies to enhance plasticity in the developing and mature brain, potentially allowing treatments for central visual dysfunction and other intractable brain disorders.