Paul Worley

The focus of our research is to identify mechanisms of protein synthesis-dependent neuronal 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 candiate genes that are involved in this response. Over the past several years, we have examined the composition and contribution of these genes to neuronal function. Gene products that are linked to protein synthesis dependent plasticity include transcription factors, cytoskeletal proteins, growth factors, metabolic enzymes and proteins involved in signal transduction. The biochemical and cell biological properties of these molecules provide important insights into mechanisms that contribute to neuronal plasticity. Currently, we are focusing on a subset of immediate early genes that function directly at the excitatory synapse; these include Homer, Arc, and Narp. Homer binds and modifies the signaling of group 1 metabotropic glutamate receptors and ion channels that regulated intracellular stores of calcium. Arc functions as a regulatory factor for an endocytosis pathway that selectively traffics AMPA type glutamate receptors and mediates homeostatic scaling of neuronal excitability. Narp functions as an extracellular aggregating factor that binds AMPA receptors and plays a role in excitatory synaptogenesis. Animal models that delete or modify the function of these proteins identify important roles in learning and memory, drug addiction and inflammatory pain. These studies provide insight into how rapid transcriptional events can contribute to synapse-specific plasticity in normal and pathological conditions.