The role of histone acetyltransferases in memory storage and synaptic plasticity Synaptic plasticity, the change in the strength of neuronal connections in the brain, is thought to underlie memory storage and may play a crucial role in a variety of neurological and mental disorders, including Alzheimer's disease, mental retardation, epilepsy and depression. One form of synaptic plasticity that has received much attention is long-term potentiation (LTP), an activity-dependent form of synaptic enhancement. Like long-term memory storage, long-lasting forms of LTP differ from short-term potentiation in requiring protein synthesis, and transcription. Protein kinase A (PKA) acts along with other kinases to activate transcription factors such as cAMP response element binding protein (CREB), leading to gene induction and long-term memory storage. The regulation of gene expression, however, requires not only sequence-specific transcription factors like CREB, but also transcriptional coactivators, such as the paralogous factors CREB- binding protein (CBP) and p300. CBP and p300 are potent histone acetyltransferases (HATs) that coordinately regulate gene activity in a cell type- and promoter-specific fashion by modifying chromatin structure. Much of the work in memory storage and synaptic plasticity has been focused on CBP. CBP mutant and transgenic dominant negative mice show deficits in spatial learning, and in hippocampal LTP paradigms. However, work on p300 dominant negative transgenic mice and p300 conditional knockouts also show a role for p300 in spatial memory. A common loss-of-function genetic manipulation has not been used to study both CBP and p300, in order to dissect the requirement of these HATs in memory storage. This project aims to use a targeted approach that would result in a spatially restricted deletion of CBP, p300 or both in the hippocampus, through the use of a viral vector. This approach serves two purposes: one is to have a common manipulation to assess the different and overlapping roles of the paralogues, and the other is to determine if the locus of action of each of these factors is the hippocampus. The proposal has three aims: the first is to look at the electrophysiology in these targeted deletion mutants;specifically looking at cAMP-, and PKA-dependent, and PKA-independent LTP paradigms in the Schaffer collateral synapse.
The second aim i s to look at the behavioral phenotypes of these animals, especially in hippocampus-dependent tasks such as contextual fear conditioning, and spatial object recognition. Finally, the third aim is to look at target gene expression and chromatin acetylation of these genes in these mutants, before and after a learning paradigm. These studies would allow us to compare the different and overlapping targets of these two paralogous HATs, and help in the understanding of activity-dependent gene activation in the neuron during memory storage.
(Relevance) Long-term memory storage and long-lasting forms of synaptic plasticity involve the coordinate regulation of gene expression, but the mechanisms by which this transcriptional regulation is accomplished are only beginning to be understood. We propose experiments to examine the role of transcriptional co-activators and histone acetylation in gene regulation. These forms of transcriptional regulation integrate multiple signaling pathways in the coordinated regulation of gene expression. Understanding the role of histone acetylation in memory storage and synaptic plasticity may ultimately lead to the development of new treatments for disorders such as schizophrenia, neurodegenerative diseases, intellectual disability and depression.