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.
|Hawk, Joshua D; Bookout, Angie L; Poplawski, Shane G et al. (2012) NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors. J Clin Invest 122:3593-602|
|Hawk, Josh D; Abel, Ted (2011) The role of NR4A transcription factors in memory formation. Brain Res Bull 85:21-9|
|Hernandez, Pepe J; Abel, Ted (2011) A molecular basis for interactions between sleep and memory. Sleep Med Clin 6:71-84|
|Hawk, Joshua D; Florian, Cedrick; Abel, Ted (2011) Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory. Learn Mem 18:367-70|
|Hellman, Kevin; Hernandez, Pepe; Park, Alice et al. (2010) Genetic evidence for a role for protein kinase A in the maintenance of sleep and thalamocortical oscillations. Sleep 33:19-28|
|Havekes, Robbert; Abel, Ted (2009) Genetic dissection of neural circuits and behavior in Mus musculus. Adv Genet 65:1-38|
|Lee, Jeong-Sik; Jang, Deok-Jin; Lee, Nuribalhae et al. (2009) Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors. J Neurosci 29:8493-505|
|Hock, Brian J; Lattal, K Matthew; Kulnane, Laura Shapiro et al. (2009) Pathology associated memory deficits in Swedish mutant genome-based amyloid precursor protein transgenic mice. Curr Aging Sci 2:205-13|
|Kelly, M P; Stein, J M; Vecsey, C G et al. (2009) Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Galphas, a G-protein subunit genetically linked to schizophrenia. Mol Psychiatry 14:398-415, 347|
|Hernandez, Pepe J; Abel, Ted (2008) The role of protein synthesis in memory consolidation: progress amid decades of debate. Neurobiol Learn Mem 89:293-311|
Showing the most recent 10 out of 41 publications