title: Electrophysiological effects of melatonin on mouse Per1 and non-Per1 suprachiasmatic nuclei neurones in vitro.
abstract: The master circadian pacemaker in the suprachiasmatic nuclei (SCN) regulates the nocturnal secretion of the pineal hormone melatonin. Melatonin, in turn, has feedback effects on SCN neuronal activity rhythms via high affinity G protein-coupled receptors (MT(1) and MT(2) ). However, the precise effects of melatonin on the electrical properties of individual SCN neurones are unclear. In the present study, we investigated the acute effects of exogenous melatonin on SCN neurones using whole-cell patch-clamp recordings in brain slices prepared from Per1::d2EGFP-expressing transgenic mice. In current-clamp mode, bath applied melatonin, at near-physiological concentrations (1 nM), hyperpolarised the majority (63.7%) of SCN neurones tested at all times of the projected light/dark cycle. In addition, melatonin depolarised a small proportion of cells (11.0%). No differences were observed for the effects of melatonin between Per1::GFP or non-Per1::GFP SCN neurones. Melatonin-induced effects were blocked by the MT(1)/MT(2) antagonist, luzindole (1 μM) and the proportion of SCN neurones responsive to melatonin was greatly reduced in the presence of either tetrodotoxin (200 or 500 nM) or gabazine (20 μM). In voltage-clamp recordings, 1 nM melatonin increased the frequency of GABA-mediated currents. These findings indicate, for the first time, that exogenous melatonin can alter neuronal excitability in the majority of SCN neurones, regardless of whether or not they overtly express the core clock gene Per1. The results also suggest that melatonin acts mainly by modulating inhibitory GABAergic transmission within the SCN. This may explain why exogenous application of melatonin has heterogenous effects on individual SCN neurones.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK .
authors.forename: F F
authors.initials: FF
authors.lastname: Scott
authors.forename: M D C
authors.initials: MD
authors.lastname: Belle
authors.forename: P
authors.initials: P
authors.lastname: Delagrange
authors.forename: H D
authors.initials: HD
authors.lastname: Piggins
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D055724:Electrophysiological Phenomena; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D056950:Period Circadian Proteins / Q000235:genetics*; D011724:Pyridazines / Q000494:pharmacology; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors; D011963:Receptors, GABA-A / Q000187:drug effects; D013493:Suprachiasmatic Nucleus / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D018756:GABA Antagonists; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D011724:Pyridazines; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011963:Receptors, GABA-A; D014363:Tryptamines; C057154:luzindole; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C049853:gabazine; D008550:Melatonin