Research

The focus of our research is to identify mechanisms of activity-dependent neural plasticity. The approach uses differential cloning techniques to identify mRNAs that are rapidly induced in neurons by synaptic activity. Classical studies established that rapid, de novo protein synthesis is required for long-term memory, and we developed animal models that maximize the induction of candidate genes that are involved in this response.

Outline of Projects

Over the past several years, we have examined the composition and functional contribution of these genes to neural function. Gene products that are linked to protein synthesis dependent plasticity include a transcription factor (egr3), a cytoskeletal protein (arc), a small G-protein (rheb), metabolic enzymes (COX-2 and mPGES) and a cell adhesion molecule (arcadlin). The biochemical and cell biological properties of these molecules provide important insights into mechanisms that contribute to neural plasticity. Because many of the immediate early gene proteins are novel, we have made extensive use of the yeast 2-hybrid system to establish interacting networks of proteins. Perhaps most interestingly, we have identified a subset of immediate early genes that appear to function directly at the excitatory synapse (Neuron 1993; J Biol Chem. 1994; Neuron 1995; Am J Physiol. 1997; J Biol Chem. 1999; J Biol Chem. 2000; J Neurosci. 2001). These studies provide insight into how rapid transcriptional events, that are induced in models of learning and memory, can contribute to synapse-specific plasticity.

Induction of arcadlin mRNA in the hippocampal granule cells after maximal electro-convulsive seizure (MECS) (a) and during LTP (b). C, unstimulated; S, MECS-stimulated. LF, low frequency; HF, high frequency stimulated

Staff