The CRE/CREB Pathway and Visual Cortical Plasticity

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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.