GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior

Significance

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 γ-aminobutyric acid (GABA) as a neurotransmitter, the physiological roles of GABA in the SCN network are poorly understood. We show that mice lacking GABA release specifically from arginine vasopressin (AVP)-producing neurons, one of the major neuron types in the SCN, retain an SCN that progresses normally at the clock gene level but fires aberrantly with bimodal rhythm. Accordingly, the mice demonstrate locomotor activity at inappropriate times with respect to the clock gene-based SCN clock. GABAergic transmission from AVP neurons may regulate SCN firing rhythm to modulate when SCN molecular clocks enable daily behavior.

Abstract

The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. 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 GABA _A 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 Ca ²⁺ 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. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks.