Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling

TLDR

The suprachiasmatic nucleus (SCN) orchestrates daily physiological and behavioral rhythms, with intrinsic circadian oscillations of gene expression and electrical activity that persist independently of external cues. The study demonstrates that SCN neurons constitute only the daytime‑active half of the circadian clock. SCN astrocytes, active at night, suppress neuronal activity by modulating extracellular glutamate, which is sensed by dorsal SCN neurons through NR2C‑containing NMDA receptors. Reprogramming astrocyte clocks remodels circadian behavior, revealing that SCN timekeeping depends on reciprocal astrocyte–neuron signaling.

Abstract

The suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms of physiology and behavior in mammals. Its circadian (∼24 hr) oscillations of gene expression and electrical activity are generated intrinsically and can persist indefinitely in temporal isolation. This robust and resilient timekeeping is generally regarded as a product of the intrinsic connectivity of its neurons. Here we show that neurons constitute only one "half" of the SCN clock, the one metabolically active during circadian daytime. In contrast, SCN astrocytes are active during circadian nighttime, when they suppress the activity of SCN neurons by regulating extracellular glutamate levels. This glutamatergic gliotransmission is sensed by neurons of the dorsal SCN via specific pre-synaptic NMDA receptor assemblies containing NR2C subunits. Remarkably, somatic genetic re-programming of intracellular clocks in SCN astrocytes was capable of remodeling circadian behavioral rhythms in adult mice. Thus, SCN circuit-level timekeeping arises from interdependent and mutually supportive astrocytic-neuronal signaling.