Spike and Neuropeptide-Dependent Mechanisms Control GnRH Neuron Nerve Terminal Ca over Diverse Time Scales

Fast cell-to-cell communication in the brain is achieved by action potential-dependent synaptic release of neurotransmitters. The fast kinetics of transmitter release are determined by transient Ca elevations in presynaptic nerve terminals. Neuromodulators have previously been shown to regulate transmitter release by inhibiting presynaptic Ca influx. Few studies to date have demonstrated the opposite, that is, neuromodulators directly driving presynaptic Ca rises and increases in nerve terminal excitability. Here we use GCaMP Ca imaging in brain slices from mice to address how nerve terminal Ca is controlled in gonadotropin-releasing hormone (GnRH) neurons via action potentials and neuromodulators. Single spikes and bursts of action potentials evoked fast, voltage-gated Ca channel-dependent Ca elevations. In contrast, brief exposure to the neuropeptide kisspeptin-evoked long-lasting Ca plateaus that persisted for tens of minutes. Neuropeptide-mediated Ca elevations were independent of action potentials, requiring Ca entry via voltage-gated Ca channels and transient receptor potential channels in addition to release from intracellular store mechanisms. Together, these data reveal that neuromodulators can exert powerful and long-lasting regulation of nerve terminal Ca independently from actions at the soma. Thus, GnRH nerve terminal function is controlled over disparate timescales via both classical spike-dependent and nonclassical neuropeptide-dependent mechanisms. Nerve terminals are highly specialized regions of a neuron where neurotransmitters and neurohormones are released. Many neuroendocrine neurons release neurohormones in long-duration bursts of secretion. To understand how this is achieved, we have performed live Ca imaging in the nerve terminals of gonadotropin-releasing hormone neurons. We find that bursts of action potentials and local neuropeptide signals are both capable of evoking large increases in nerve terminal Ca Increases in Ca driven by spike bursts last seconds; however, the increases in nerve terminal Ca driven by neuropeptides can persist for tens of minutes. These findings reveal new mechanisms by which neuroendocrine nerve terminal Ca can be controlled in the brain.