While the ability of neurotrophins to modulate synaptic function in the short-term (minutes to hours) has been extensively studied in recent years, very much less is known about the potential roles neurotrophins play in regulating longer-term forms of synaptic modification that may occur over the time frame of days to weeks or more. A key issue is whether such long-term roles for neurotrophins are essentially supportive, resembling the traditional roles of neurotrophins in promoting neuronal survival and differentiation in the peripheral nervous system. In this case, neurotrophins would simply allow, by their presence and action, other signaling processes to encode information and change in neural circuits. Alternatively, neurotrophins may selectively regulate key elements of excitable and synaptic function and thereby directly mediate important aspects of synaptic plasticity. The goal of this proposal is thus to distinguish between these two alternatives in understanding how neuronal and neural circuit function is regulated by neurotrophins in the long-term. To this end, the three Specific Aims of the proposal will determine, using a combination of molecular biological and electrophysiological approaches in primary neuronal culture, if neurotrophin regulation of excitable and synaptic function shows: selectivity, that a given neurotrophin regulates only particular aspects of excitable and synaptic function in a target neuron; neurotrophin-specificity, that neurotrophins each induce distinct functional changes in a given target neuron, even when that neuron responds to multiple factors; and activity-dependence, a way in which neurotrophin action can be linked to particular modes and patterns of electrical and/or synaptic activity. These experiments will contribute to our understanding of how neurotrophins parLicipate in regulating synaptic plasticity and how deficiencies in neurotrophin signaling can lead to neuronal dysfunction and neurological disorders.
