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The mechanism setting ON/OFF timer in the master circadian clock.
Takashi Maejima (Michihiro Mieda)

In mammals, the suprachiasmatic nucleus (SCN) functions as the master circadian clock to orchestrate multiple circadian biological rhythms in the body. Although almost all SCN neurons contain GABA as a neurotransmitter, the physiological roles of GABA in the SCN network are poorly understood. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABAA receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca2+ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. These data suggest that GABAergic transmission from AVP neurons shapes the SCN neuronal activity rhythm to coordinate the time at which the SCN molecular clocks allow the animal’s daily behavior. Thus, we propose an additional regulatory layer of circadian pattern formation on the molecular clocks in the SCN. (221 words)

GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior. Maejima T, Tsuno Y, Miyazaki S, Tsuneoka Y, Hasegawa E, Islam MT, Enoki R, Nakamura TJ, Mieda M. (2021) PNAS 118 (6): e2010168118 (https://doi.org/10.1073/pnas.2010168118)

A schema summarizing the effects caused by the deficiency of GABAergic transmission from AVP neurons on circadian rhythms at multiple levels. Without GABA release from AVP neurons, the spatiotemporal pattern of GABAergic transmission alters within the SCN. Such an alteration does not significantly disturb the spatiotemporal organization of molecular clocks measured with clock gene expression and [Ca2+]i, but it does cause an aberrant bimodal pattern of the SCN firing rhythm that may lead to the increased interval between the morning and evening locomotor activities. Thus, GABAergic transmission of AVP neurons regulates the SCN neuronal activity rhythm to modulate the time at which SCN molecular clocks enable circadian behavior.

Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, Japan.