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We are investigating the regulation of gene expression following firing of the postsynaptic neuron correlated or uncorrelated with synaptic activity, and the significance of activity-dependent transcription of these genes in establishing enduring neuronal plasticity. Our work shows the importance of temporal and spatial segregation of intracellular signaling pathways, involving calcium, CREB, MAPK, and immediate early genes in activating gene transcription associated with long-term changes in synaptic strength. Using microarrays we have identified sets of transcription factors, structural genes, and signaling pathways that are regulated by activity patterns leading selectively to different types of synaptic plasticity. One finding of particular interest is that expression of the gene BDNF, which encodes a growth factor, depends on whether firing of postsynaptic hippocampal CA1 neurons is coincident with excitatory synaptic firing from presynaptic neurons.