Angiotensin II regulates the activity of mouse suprachiasmatic nuclei neurons

Neuropeptide signaling plays key roles in coordinating cellular activity within the suprachiasmatic nuclei (SCN), site of the master circadian oscillator in mammals. The neuropeptide angiotensin If (ANGII) and its cognate receptor AT(1) are both expressed by SCN cells, but unlike other SCN neurochemicals, very little is known about the cellular actions of ANGII within this circadian clock. We used multi-electrode, multiunit, extracellular electrophysiology, coupled with whole-cell voltage and current clamp techniques to investigate the actions of ANGII in mouse SCN slices. ANGII (0.001-10 mu M) dose dependently stimulated and inhibited extracellularly recorded neuronal discharge in many SCN neurons (similar to 60%). Both actions were blocked by pre-treatment with the AT(1) receptor antagonist ZD7155 (0.03 mu M), while suppressions but not activations were prevented by pre-treatment with the GABA(A) receptor antagonist bicuculline (20 mu M). AT(1) receptor blockade itself suppressed discharge in a subset (similar to 30%) of SCN neurons, and this action was not blocked by bicuculline. In voltage-clamped SCN neurons (-70 mV), AT(1) receptor activation dose-dependently enhanced the frequency of action potential-driven, GABAA receptor-mediated currents, but did not alter their responses to exogenously applied GABA. In current-clamped SCN neurons perfused with tetrodotoxin, ANGII induced a membrane depolarization with a concomitant decrease in input resistance. In conclusion we show that AT(1) receptor activation by ANGII depolarizes SCN neurons and stimulates action potential firing, leading to increased GABA release in the mouse SCN. Additionally we provide the first evidence that endogenous AT(1) receptor signaling tonically regulates the activities of some SCN neurons. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.