Synaptic plasticity, the activity-dependent change in the strength of neuronal connections, is thought to underlie memory storage and may play an important role in several neurological and psychiatric disorders. A number of critical cellular and molecular events that mediate synaptic plasticity and memory have been identified. The cAMP-dependent protein kinase (PKA) signaling pathway is required for long-lasting forms of hippocampal long-term potentiation (LTP), a well-studied type of synaptic plasticity, and for long-term memory storage. A hallmark of long-lasting forms of synaptic plasticity, such as the late phase of LTP (L-LTP), is the activation of gene expression by PKA and other kinases via transcription factors such as the cAMP response element binding protein (CREB). The regulation of gene expression, however, requires not only sequence-specific transcription factors like CREB, but also transcriptional coactivators, such as CREB- binding protein (CBP). Our previous research explored the roles that PKA, CREB and protein synthesis play in synaptic plasticity and long-term memory. In this competing renewal, we will examine the downstream effects of PKA activation of CREB by studying the function of the transcriptional coactivator CBP and its histone acetyltransferase activity in long-term memory and synaptic plasticity. Histone acetylation by CBP modulates chromatin structure and thereby alters gene activity in a cell type- and promoter-specific fashion. To define the role of CBP in memory and synaptic plasticity, we will examine two distinct mutations in cbp: one allele that impairs the ability of CBP to acetylate histones and another allele that impairs the ability of CBP to interact with transcription factors such as CREB.
In Specific Aim 1, we will use genetically modified mice to determine the role of CBP in learning and memory.
In Specific Aim 2, we will use genetically modified mice to determine the function of CBP in hippocampal synaptic plasticity.
In Specific Aim 3, we will examine the effect of the genetic manipulations of CBP on gene expression, by determining the effect of mutations of CBP on histone acetylation, CRE-mediated transcription, and the expression of CRE-containing target genes.
In Specific Aim 4, we will use histone deacetylase inhibitors to examine the effect of histone hyperacetylation on memory and synaptic plasticity. With the combination of genetic, biochemical, molecular, and pharmacological studies outlined in this grant proposal, we hope to define the role of CBP and histone acetylation in memory storage and synaptic plasticity. ? ?
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