Classical studies have demonstrated a critical role for neuronal activity in normal cortical development and plasticity. Developmental plasticity appears similar in many respects to other forms of experimental neuroplasticity, however the molecular basis for the long- term adaptive response remains to be determined. Recent studies indicate that physiological activity can induce a rapid genomic response in neurons. Genes known to be activated in this response code for transcription factors, suggesting that the genomic response may play a regulatory role in neuronal plasticity. Similar regulatory gene responses are observed in a variety of cell types and are believed to underlie cellular growth and differentiation. In fact, insights into neuronal physiology have been achieved using molecular tools initially developed in studies of cultured fibroblasts and PC12 cells. Precedent from these culture systems indicate that the initial genomic response includes an array of molecules in addition to transcription factors including cytokines, transmembrane signalling molecules and cellular matrix proteins. It is notable, that of the set of rapid response genes clones from stimulated fibroblasts only transcription factors are induced in brain suggesting that these other molecules may define the cellular specificity of the response. The focus of this proposal is to identify novel neuronal genes involved in the initial response to activity. Based on precedent from culture systems, it is anticipated that these genes will code for proteins involved in regulating adaptive neuronal responses. I have used a differential cloning strategy to identify a set of six novel genes that are induced by physiological activity in the developing visual cortex. Preliminary data indicate that these genes may be neuron specific. As a first step in defining their function, full length cDNAs will be cloned, sequenced and analyzed for predicted structure and homology to previously identified genes (Aim 1) Unique regions of the predicted amino acid sequence will be expressed as bacterial fusion proteins for generation of specific antisera (Aim 2). With these tools, we will examine the regulation of the mRNA and presumed protein products during normal development and in the visual cortex in response to synaptic activity. These studies are likely to provide new tools and insights into the molecular basis of developmental plasticity.
