Histamine resets the circadian clock in the suprachiasmatic nucleus through the H1R-Cav1.3-RyR pathway in the mouse

Histamine, a neurotransmitter/neuromodulator implicated in the control of arousal state, exerts a potent phase-shifting effect on the circadian clock in the rodent suprachiasmatic nucleus (SCN). In this study, the mechanisms by which histamine resets the circadian clock in the mouse SCN were investigated. As a first step, Ca2+-imaging techniques were used to demonstrate that histamine increases intracellular Ca2+ concentration ([Ca2+](i)) in acutely dissociated SCN neurons and that this increase is blocked by the H1 histamine receptor (H1R) antagonist pyrilamine, the removal of extracellular Ca2+ and the L-type Ca2+ channel blocker nimodipine. The histamine-induced Ca2+ transient is reduced, but not blocked, by application of the ryanodine receptor (RyR) blocker dantrolene. Immunohistochemical techniques indicated that Ca(v)1.3 L-type Ca2+ channels are expressed mainly in the somata of SCN cells along with the H1R, whereas Ca(v)1.2 channels are located primarily in the processes. Finally, extracellular single-unit recordings demonstrated that the histamine-elicited phase delay of the circadian neural activity rhythm recorded from SCN slices is blocked by pyrilamine, nimodipine and the knockout of Ca(v)1.3 channel. Again, application of dantrolene reduced but did not block the histamine-induced phase delays. Collectively, these results indicate that, to reset the circadian clock, histamine increases [Ca2+] i in SCN neurons by activating Ca(v)1.3 channels through H1R, and secondarily by causing Ca2+-induced Ca2+ release from RyR-mediated internal stores.