The goal of this study is to investigate the signal transduction and transcriptional events that underlie long-term memory (LTM) formation. Previous work has shown that the expression of genes regulated by a cis-acting element, the cAMP response element (CRE), is induced in the hippocampus during LTM formation. The first two specific aims of this proposal use pharmacological inhibitors and viral vectors to test the necessity of two elements of the signal transduction cascade that is hypothesized to promote this transcriptional activity. One of these elements, the N-methyl-D-aspartate (NMDA) receptor, is required for LTM formation but not the induction of CRE-mediated transcription during long-term potentiation (LTP). LTP is an electrophysiological model for the changes in synaptic efficacy that are hypothesized to occur during LTM formation. The second element, mitogen-activated protein kinase (MAPK), has been recently shown to be necessary for the induction of CRE-mediated gene expression by LTP. Preliminary evidence suggests that both of these elements are required for LTM formation and the consequent induction of CRE-dependent transcription.
The specific aim of this proposal is to test the necessity of CRE-mediated expression in LTM formation directly using decoy oligonucleotides. These are important investigations because they will further our understanding of the biochemistry of memory formation. This will be critical to the successful development of treatments for both disease- and aging-related memory dysfunctions.
| Pineda, Victor V; Athos, Jaime I; Wang, Hongbing et al. (2004) Removal of G(ialpha1) constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation. Neuron 41:153-63 |
| Wang, Hongbing; Chan, Guy C-K; Athos, Jaime et al. (2002) Synaptic concentration of type-I adenylyl cyclase in cerebellar neurons. J Neurochem 83:946-54 |
| Athos, Jaime; Impey, Soren; Pineda, Victor V et al. (2002) Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci 5:1119-20 |
