title: Spike and Neuropeptide-Dependent Mechanisms Control GnRH Neuron Nerve Terminal Ca2+over Diverse Time Scales.
abstract: 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 Ca2+elevations in presynaptic nerve terminals. Neuromodulators have previously been shown to regulate transmitter release by inhibiting presynaptic Ca2+influx. Few studies to date have demonstrated the opposite, that is, neuromodulators directly driving presynaptic Ca2+rises and increases in nerve terminal excitability. Here we use GCaMP Ca2+imaging in brain slices from mice to address how nerve terminal Ca2+is controlled in gonadotropin-releasing hormone (GnRH) neurons via action potentials and neuromodulators. Single spikes and bursts of action potentials evoked fast, voltage-gated Ca2+channel-dependent Ca2+elevations. In contrast, brief exposure to the neuropeptide kisspeptin-evoked long-lasting Ca2+plateaus that persisted for tens of minutes. Neuropeptide-mediated Ca2+elevations were independent of action potentials, requiring Ca2+entry via voltage-gated Ca2+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 Ca2+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.SIGNIFICANCE STATEMENTNerve 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 Ca2+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 Ca2+Increases in Ca2+driven by spike bursts last seconds; however, the increases in nerve terminal Ca2+driven by neuropeptides can persist for tens of minutes. These findings reveal new mechanisms by which neuroendocrine nerve terminal Ca2+can be controlled in the brain.
authors.affiliation: Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin 9054, New Zealand karl.iremonger@otago.ac.nz.
authors.forename: Karl J
authors.identifier: 0000-0002-8976-2401
authors.initials: KJ
authors.lastname: Iremonger
authors.affiliation: Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin 9054, New Zealand.
authors.forename: Robert
authors.initials: R
authors.lastname: Porteous
authors.affiliation: Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin 9054, New Zealand.
authors.forename: Allan E
authors.identifier: 0000-0002-9615-3022
authors.initials: AE
authors.lastname: Herbison
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000502:physiology*; D013997:Time Factors
chemical_list: D009479:Neuropeptides; D007987:Gonadotropin-Releasing Hormone; D002118:Calcium
keywords: GnRH; calcium; kisspeptin; median eminence; nerve terminal