title: Cholinergic modulation of neuronal excitability in the rat suprachiasmatic nucleus.
abstract: The central cholinergic system regulates both the circadian clock and sleep-wake cycle and may participate in the feedback control of vigilance states on neural excitability in the suprachiasmatic nucleus (SCN) that houses the circadian clock. Here we investigate the mechanisms for cholinergic modulation of SCN neuron excitability. Cell-attached recordings indicate that the nonspecific cholinergic agonist carbachol (CCh) inhibited 55% and excited 21% SCN neurons, leaving 24% nonresponsive. Similar response proportions were produced by two muscarinic receptor [muscarinic acetylcholine receptor (mAChR)] agonists, muscarine and McN-A-343 (M1/4 agonist), but not by two nicotinic receptor (nAChR) agonists, nicotine and choline (alpha7-nAChR agonist), which, however, produced similar response proportions. Whole cell and perforated-patch recordings indicate that CCh inhibition of firing was mediated by membrane hyperpolarization due to activation of background K(+) currents, which were sensitive to submillimolar concentrations of Ba(2+) and to millimolar concentrations of TEA. RT-PCR analysis demonstrated the presence of mRNA for M1 to M5 mAChRs in SCN. The CCh-induced hyperpolarization and activation of background K(+) currents were blocked by M4 antagonists and to a lesser degree by M1 antagonists but were insensitive to the antagonists for M2 or M3, suggesting the involvement of M4 and M1 mAChRs in mediating CCh inhibition of firing. CCh enhancement of firing was mediated by membrane depolarization, as a result of postsynaptic inhibition of background K(+) currents. The multiple actions of cholinergic modulation via multiple receptors and ion channels may allow acetylcholine to finely control SCN neuron excitability in different physiological settings.
authors.affiliation: Dept. of Physiology and Pharmacology, Chang Gung University School of Medicine, Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Jyh-Jeen
authors.initials: JJ
authors.lastname: Yang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Pi-Cheng
authors.initials: PC
authors.lastname: Cheng
authors.forename: Yeh-Jung
authors.initials: YJ
authors.lastname: Kuo
authors.forename: Rong-Chi
authors.initials: RC
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D043588:Receptor, Muscarinic M4 / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013493:Suprachiasmatic Nucleus / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D018721:Muscarinic Agonists; D015221:Potassium Channels; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D005680:gamma-Aminobutyric Acid; D002217:Carbachol