Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

• Published in: Cell reports (Cambridge) Vol. 25; no. 1; pp. 1 - 9.e5
• Main Authors: Lananna, Brian V., Nadarajah, Collin J., Izumo, Mariko, Cedeño, Michelle R., Xiong, David D., Dimitry, Julie, Tso, Chak Foon, McKee, Celia A., Griffin, Percy, Sheehan, Patrick W., Haspel, Jeffery A., Barres, Ben A., Liddelow, Shane A., Takahashi, Joseph S., Karatsoreos, Ilia N., Musiek, Erik S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-10-2018; Elsevier
• Subjects: Animals; ARNTL Transcription Factors; astrocyte; Astrocytes - cytology; Astrocytes - metabolism; astrogliosis; Bmal1; Cell Death - physiology; circadian; Circadian Clocks - genetics; Circadian Clocks - physiology; Female; glutathione; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; neuroinflammation; Primary Cell Culture; rhythm; Transfection; circadian; neuroinflammation; glutathione; astrogliosis; rhythm; astrocyte; Bmal1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.09.015

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.
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•Circadian disruption promotes astrocyte activation•Astrocyte-specific deletion of the circadian clock gene BMAL1 induces activation•BMAL1 regulates astrocyte activation by altering glutathione-S-transferase signaling•Loss of astrocyte BMAL1 enhances neuronal cell death in a co-culture system
Lananna et al. show that the circadian clock protein BMAL1 regulates astrocyte activation via a cell-autonomous mechanism involving diminished glutathione-S-transferase signaling. This finding elucidates a function of the core circadian clock in astrocytes and reveals BMAL1 as a modulator of astrogliosis.