Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle

• Published in: Neuron (Cambridge, Mass.) Vol. 95; no. 6; pp. 1365 - 1380.e5
• Main Authors: Clasadonte, Jerome, Scemes, Eliana, Wang, Zhongya, Boison, Detlev, Haydon, Philip G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-09-2017; Elsevier Limited
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; astrocytic metabolic networks; Brain; Connexin 43; Connexin 43 - genetics; Connexin 43 - physiology; Cre recombinase; EEG; Eye movements; gap junction; Gap Junctions - physiology; Glucose; Glucose - metabolism; Hypothalamic Area, Lateral - metabolism; Hypothalamic Area, Lateral - physiology; Hypothalamus; Hypothalamus (lateral); lactate; Lactic acid; Lactic Acid - metabolism; Lactic Acid - pharmacology; Liquid oxygen; Metabolic networks; Metabolism; Metabolites; Mice; Mice, Knockout; Neurons; Neurons - metabolism; Neurons - physiology; Nocturnal; orexin neuron; Orexins; Orexins - genetics; Orexins - physiology; Physiology; Rodents; Sleep - physiology; Sleep and wakefulness; Sleep disorders; sleep-wake cycle; Sleepiness; Wakefulness; Wakefulness - physiology; orexin neuron; sleep-wake cycle; gap junction; lactate; astrocytic metabolic networks; EEG
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.08.022

Astrocytes produce and supply metabolic substrates to neurons through gap junction-mediated astroglial networks. However, the role of astroglial metabolic networks in behavior is unclear. Here, we demonstrate that perturbation of astroglial networks impairs the sleep-wake cycle. Using a conditional Cre-Lox system in mice, we show that knockout of the gap junction subunit connexin 43 in astrocytes throughout the brain causes excessive sleepiness and fragmented wakefulness during the nocturnal active phase. This astrocyte-specific genetic manipulation silenced the wake-promoting orexin neurons located in the lateral hypothalamic area (LHA) by impairing glucose and lactate trafficking through astrocytic networks. This global wakefulness instability was mimicked with viral delivery of Cre recombinase to astrocytes in the LHA and rescued by in vivo injections of lactate. Our findings propose a novel regulatory mechanism critical for maintaining normal daily cycle of wakefulness and involving astrocyte-neuron metabolic interactions.
•Cx43-mediated gap junctions are functional in the lateral hypothalamus•Astroglial Cx43 permit lactate shuttling from astrocytic networks to orexin neurons•Knockout of astroglial Cx43 silences orexin neurons, causing wakefulness instability•Lactate delivery to the lateral hypothalamic area rescues normal wakefulness
Astrocytes supply energy metabolites to neurons, but how this influences behavior is unclear. Clasadonte et al. demonstrate that delivery of lactate from astrocytes to neurons is required for normal orexinergic neuronal activity and hence daily cycles of wakefulness.