Effects of VPAC2 Receptor Activation on Membrane Excitability and GABAergic Transmission in Subparaventricular Zone Neurons Targeted by Suprachiasmatic Nucleus

Neurosciences, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Ontario, Canada Submitted 26 November 2008; accepted in final form 24 June 2009 Abstract The hypothalamic suprachiasmatic nucleus (SCN) harbors the master circadian pacemaker. SCN neurons produce the amino acid -aminobutyric acid (GABA) and several peptide molecules for coordination and communication of their circadian rhythms. A subpopulation of SCN cells synthesizes vasoactive intestinal polypeptide (VIP) and provides a dense innervation of the subparaventricular zone (SPZ), an important CNS target of the circadian pacemaker. In this study, using patch-clamp recording techniques and rat brain slice preparations, the contribution of VIP to SCN efferent signaling to SPZ was evaluated by examining membrane responses of SPZ neurons to exogenous VIP receptor ligands. In 50% of the SPZ neurons receiving monosynaptic GABA A receptor–mediated inputs from SCN, bath-applied VIP (0.5–1 µM) resulted in a membrane depolarization caused by tetrodotoxin-resistant inward currents reversing at –23 mV. These data suggest the existence of postsynaptic receptors that activate a nonselective cationic conductance. In addition, a subset of SPZ neurons showed an increase in the amplitude of SCN-evoked GABAergic inhibitory postsynaptic currents (IPSCs) and a decrease in their paired-pulse ratios. This, together with an increase in frequency of spontaneous and miniature IPSCs, implies the presence of presynaptic receptors that facilitate GABA release from SCN and possibly other synaptic terminals. The effects occurred in separate neurons and could be mimicked by the selective VPAC 2 receptor agonist BAY 55-9837 (0.2–0.5 µM) and partially blocked by the VIP receptor antagonist VIP(6-28) (5 µM). The results indicate that VIP acts via both post- and presynaptic VPAC 2 receptors to differentially modulate SCN GABAergic signaling to distinct subpopulations of SPZ neurons. Address for reprint requests and other correspondence: L. P. Renaud, Neurosciences, Ottawa Hospital Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9 (E-mail: lprenaud{at}ohri.ca )