title: Astrocytes Control Circadian Timekeeping in the Suprachiasmatic Nucleus via Glutamatergic 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.
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: marcob@mrc-lmb.cam.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Brancaccio
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Patton
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Chesham
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Maywood
authors.affiliation: Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address: mha@mrc-lmb.cam.ac.uk.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000502:physiology*
chemical_list: C432823:NR2C NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
keywords: GABA; NMDAR2C; SCN; astrocytic-neuronal interactions; calcium oscillations; circadian; circadian behavior; circuit synchronization; extracellular glutamate; membrane potential oscillations