Activation of glycine receptor phase-shifts the circadian rhythm in neuronal activity in the mouse suprachiasmatic nucleus.

Non-technical summary  In mammals, an internal timing system in the suprachiasmatic nucleus generates circadian (24 h) rhythms and communicates its circadian signal to other brain areas by means of action potentials where it regulates our daily schedules of physiological and endocrine processes. Several input pathways of the suprachiasmatic nucleus can influence the endogenous timing system and synchronize it with environmental timing cues. We show here that the inhibitory neurotransmitter glycine can modulate the activity of clock neurons and can reset their rhythmic activity depending on the phase of the daily cycle. The knowledge of these synchronizing mechanisms is of importance for understanding the consequences of perturbations of the circadian timing system that could lead to serious health impairments. Abstract  In mammals, the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is composed of numerous synchronized oscillating cells that drive daily behavioural and physiological processes. Several entrainment pathways, afferent inputs to the SCN with their neurotransmitter and neuromodulator systems, can reset the circadian system regularly and also modulate neuronal activity within the SCN. In the present study, we investigated the function of the inhibitory neurotransmitter glycine on neuronal activity in the mouse SCN and on resetting of the circadian clock. The effects of glycine on the electrical activity of SCN cells from C57Bl/6 mice were studied either by patch-clamp recordings from acute brain slices or by long-term recordings from organotypic brain slices using multi-microelectrode arrays (MEA). Voltage-clamp recordings confirmed the existence of glycine-induced, chloride-selective currents in SCN neurons. These currents were reversibly suppressed by strychnine, phenylbenzene ω-phosphono-α-amino acid (PMBA) or ginkgolide B, selective blockers of glycine receptors (GlyRs). Long-term recordings of the spontaneous activity of SCN neurons revealed that glycine application induces a phase advance during the subjective day and a phase delay during the early subjective night. Both effects were suppressed by strychnine or by PMBA. These results suggest that glycine is able to modulate circadian activity by acting directly on its specific receptors in SCN neurons.