Target-derived neurotrophic factors are essential for the survival and differentiation of developing neurons. Recent evidence indicates that neurotrophins, a family of proteins related to nerve growth factor, may also participate in activity-dependent modification of synaptic connections. Using rat hippocampal cultures and Xenopus nerve-muscle cultures as model systems, the applicants propose to investigate the spatial and temporal properties of neurotrophic secretion and action at the synapse. In part I, the applicants will examine acute pre- and postsynaptic effects of exogenous brain-derived neurotrophic factor (BDNF) on the basal synaptic properties and activity-induced plasticity at hippocampal and neuromuscular synapses. Using local delivery of BDNF and BDNF-coated beads, the applicants will determine the spatial and temporal patterns in the BDNF action. The applicants will also examine whether electrical activity affects the action of BDNF by altering the binding, transduction, or internalization of the factor. The potential """"""""gating"""""""" and """"""""synergistic"""""""" effect of cAMP-dependent processes on the BDNF action will also be explored. In part II, the applicant will examine whether secretion of BDNF from neurons overexpressing BDNF or endogenous secretion of TrkB ligands can modulate synaptic efficacy, whether synaptic activity can trigger a localized secretion of BDNF, and whether the action of secreted BDNF is restricted to the site of BDNF secretion. The trafficking and secretion of BDNF will also be followed by using fluorescently tagged BDNF. Finally, in part III, they will examine the long-term actions of BDNF on the structure and function of the synapse, determine whether such long-term actions can retain synapse-specificity, whether active transport, Ca2+ signaling, gene activation and protein synthesis, and activation of protein kinases and phosphotases are involved in the transduction of long-term BDNF effects. Finally, the applicants will examine the possibility that selective synaptic """"""""tag"""""""" associated with long-term specific synaptic modification is due to an activity-dependent upregulation of the receptiveness of the synapse to the action of neurotrophic. Taken together, these in vitro studies provide unique opportunities to address several fundamental questions concerning the role of neurotrophic in synaptic plasticity, and promise to contribute new information relevant to our basic understanding of the nervous system.
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