Recent studies have found that the mechanisms of learning, and those of long-term potentiation (LTP), can differ, depending on induction protocol used. It has long been known that the formation of new memories and LTP require the synthesis of new proteins, a process regulated by constitutively expressed transcription factors. Disruptions of CREB, the most prominent such factor, however, have failed to completely abolish memory and synaptic plasticity, suggesting the existence of multiple transcriptional pathways. This proposal seeks to determine what the role of another transcriptional enhancer system, the serum response element (SRE), is in long-term memory and synaptic plasticity, and determine if it cooperates with the cyclic-AMP responsive element (CRE, bound by CREB) in these processes. In order to so so, experiments are proposed using mice carrying a region-specific, regulated dominant-negative SRF transgene (the core transcription factor necessary for SRE function). In addition, we propose further experiments to achieve better temporal resolution of SRE effect, using a technique for acute, high-efficiency knockdown of the entire enhancer in vivo and in vitro. Answers to the questions posed will elucidate the role of the SRE in long-term memory and synaptic plasticity, thus representing a possible therapeutic target. In addition, the acute method developed in these experiments will allow knockdown of any enhancer system in any experimental animal, which has relevance both to the study of molecules in non-manipulateable species, and to human therapies.
