A critical issue for both neuroscientists and society at large concerns the relative roles of genetics and environment in the postnatal development of the human brain. Environmental stimuli are wide ranging, from the detrimental (chemical toxicants, for example) to the beneficial (a mother's instructions), but all have the potential to influence the developmental program of a child as directed by its genome. The research done in the Synaptic and Developmental Plasticity Group focuses on determining 1) how the connections in the brain (synapses) change on a long-term basis in response to neuronal activity, 2) how synaptic plasticity during early postnatal development is different from plasticity in the adult, and 3) how experience shapes brain circuitry through synapse elimination during development. During our second year of operation, we have made significant progress in developing some of the methodologies that will be used in achieving the first of the aforementioned projects. We believe that long-term changes in synaptic efficacy require expression of new RNA and toward that end, we have focused on the regulation of gene expression by neuronal action potentials. To measure enzyme activity modulated by action potentials, we have developed a method for isolating nuclei from small amounts of brain tissue, which had first been electrically stimulated in vitro. Using this method, we have identified a high molecular weight complex of Extracellular signal Regulated Kinase (ERK) within neuronal nuclei that is phosphorylated after neuronal stimulation. We have further identified putative components of this complex and are now in the process of confirming our results with mass spectrometry. In a further effort to determine how genes are transcribed in response to neuronal activity, we have taken advantage of a method using a protein/DNA array to measure the activation states of up to 150 transcription factors. We are in the process of validating the results of these studies with electrophoretic mobility shift assays (EMSAs). These studies examining transcriptional regulation by neuronal activity will lead to an understanding of how genes required for synaptic plasticity are regulated. Together with the research goals listed above, these studies should bring us a better appreciation of how environmental factors play a role in brain development so that we may begin to address the associated problems of brain disease caused by toxicant exposure.
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