Regulation of neurotransmitter properties by target-derived neurotrophic factors

Brandeis University, Waltham MA

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Abstract

The sympathetic nervous system innervates a number of targets, including the heart, and sympathetic activity is a critical regulator of cardiac function. Sympathetic neurons form noradrenergic synapses onto heart cells resulting in excitation of myocyte function. Interestingly, these neurons also form cholinergic synapses onto themselves and are capable of releasing acetylcholine at neuron-myocyte synapses, which opposes the excitatory effects of noradrenergic transmission. The cholinergic and noradrenergic properties of these neurons are regulated by two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF promotes noradrenergic transmission via activation of Trk receptors. In contrast, BDNF acts through the p75 receptor to increase activity-dependent acetylcholine release. While extensive work has been done defining the co-transmission profile of sympathetic neurons, little is known about how co-transmission is established in the context of multiple targets or how selective availability of neurotrophic factors regulates the development of synaptic sites and the release of neurotransmitters in a target-specific manner. We will use electrophysiological and imaging approaches to examine the idea that the development of neurotransmitter properties of sympathetic neurons is locally regulated by the expression of neurotrophins at different targets and that individual neurons can maintain multiple release profiles at different synaptic sites. We will investigate the neurotrophin receptors that regulate the development of cholinergic and noradrenergic synaptic transmission and examine the role of neurotrophin signaling in the development of cholinergic synapses in vivo. By defining the developmental mechanisms that determine the level of sympathetic drive to the heart, these studies will provide a new understanding of the neural control of cardiovascular function.