Extensive evidence suggests that the synapse, the communicative organelle between neurons, plays a pivotal role in learning and memory. To begin defining epigenetic factors that potentially regulate molecular structure of the synapse, we have been studying a relatively simple model system, the rat sympathetic, superior cervical ganglion. Initially, we focused on the postsynaptic density (PSD), a disc-shaped structure in the postsynaptic neuron (see cover illustration). Previously, we found that trans-synaptic impulse activity regulates the predominant PSD protein molecule (PSDp). We now examine two related questions. Do other factors influence c synaptic structure independent of presynaptic innervation? Conversely, does denervation alter synaptic molecular structure in the hippocampus, as in the ganglion? Our studies indicate that the trophic protein, nerve growth factor, that governs sympathetic development and mature function, regulates the PSDp in normal and denervated ganglia. Consequently, synaptic structure in the periphery is, indeed, regulated by multiple factors. In the brain, fimbria-fornix lesions, which partially denervate the hippocampus, significantly reduce the hippocampal PSDp. We conclude that presynaptic innervation regulates synaptic structure in the hippocampus, as well as the periphery. More generally, epigenetic factors apparently regulate synaptic structure, potentially providing a molecular mechanism for information storage at the synapse.