Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic Signaling

Summary

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.

Highlights

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  SCN neurons are active during circadian day, but SCN astrocytes are active at night

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  Astrocytes direct circadian cycles of extracellular glutamate to inhibit SCN neurons

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  Astrocyte-derived inhibition is mediated by NMDAR2C complexes on dorsal SCN neurons

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  Genetic re-programming of the clock in SCN astrocytes reshapes circadian behavior

Abstract

Neurons of the suprachiasmatic nucleus (SCN) are responsible for circadian pacemaking in mammals. Here, Brancaccio et al. demonstrate that SCN astrocytes also possess pacemaking properties and unravel how they set circadian tempo by reciprocal timing with their neuronal partners.