A longstanding issue in environmental health is the need to understand the role the environment plays in human brain development. The brain of the neonate is particularly susceptible to disruption of the sensory environment, which can have profound effects on its physiology and morphology. Such susceptibility of the developing brain to environmental influence by sensory manipulation or to environmental toxicants is particularly pronounced during defined critical periods of postnatal life. On the one hand, this susceptibility makes the developing brain particularly vulnerable to toxic insults. On the other hand, the ?plasticity? of the connections between neurons, or synapses, is critical for refining brain circuitry during postnatal development. Similar mechanisms for changing synapses are likely to serve the basis for learning in the adult. Our primary interest, therefore, has been to determine the molecular basis of long-lasting synaptic plasticity. To understand how synaptic changes persist for a lifetime, we study how neuronal activity regulates gene transcription to consolidate synaptic changes. Evidence suggests that the long-term changes in synaptic efficacy require expression of new RNA and toward that end, we have focused on the regulation of gene transcription by neuronal action potentials. One kinase that is known to be turned on with neuronal activity is the Extracellular signal Regulated Kinase (ERK). We use nuclei isolated from small amounts of brain tissue, which had first been electrically stimulated in vitro (in the case of slices) or treated with drugs to stimulate neuronal activity (in the case of neuronal cultures). In these preparations, we have identified a high molecular weight entity reactive to antibodies against active ERK that increases after neuronal stimulation. We have further identified putative components of this complex and hypothesize that the enzyme transglutaminase, which can crosslink proteins in a calcium dependent fashion, is important in stabilizing the nuclear complexes. This process may be important in anchoring ERK pathway components in the nucleus to facilitate or direct transcription. In a related study, we have established that blockade of the N-methyl-D-aspartate receptor inhibits ERK activation by blocking action potential generation induced with certain stimulation patterns. These results establish the importance of action potentials in ERK activation in response to synaptic activity. Ongoing studies in the lab are directed toward understanding ERK-dependent modulation of transcription factors that regulate genes induced with neuronal activity. These studies examining transcriptional regulation by neuronal activity will lead to a better understanding of how genes required for synaptic plasticity are regulated. Our longer term interests are aimed at determining first, the nature of the developmental down-regulation of synaptic plasticity in the form of critical periods, and second, how neuronal activity leads to synapse elimination. We have begun to develop techniques by which activity-dependent synapse elimination during critical periods can be studied. By understanding the molecular and cellular mechanisms of synaptic plasticity during development, we may begin to understand how exposure to environmental toxicants during development can have life-long consequences on cognition and susceptibility to disease.
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