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

Abstract

SUMMARY 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.

Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice

“…Increased GFAP levels are generally regarded as hallmark of reactive glia, therefore we quantified Gfap transcripts or protein by qPCR or immunostaining, respectively, in different brain areas (cortical, hippocampal, and hypothalamic regions) of control and Bmal1cKO mice at 2 and 4 months after TM treatment. In agreement with previous reports (Lananna et al, ; Musiek et al, ; Nakazato et al, ), we did not detect the increased expression of Gfap in cortex or hippocampus 2 months after TM treatment (Figure a, Table S1). However, 4 months after TM treatment, we found increased GFAP immunoreactivity in different cortical regions and hippocampus of the mutants (Figure b and S1), confirming that Bmal1cKO s developed age‐dependent gliosis.…”

“…Next, we investigated whether the deregulation of the molecular clock in the brains of our mutants lead to reactive gliosis, as previously reported in cortex and hippocampus of constitutive Bmal1 −/−, Nestin‐Cre‐Bmal1 or Aldh1l1‐CreERT2‐Bmal1 mice (Lananna et al, ; Musiek et al, ; Nakazato et al, ). Increased GFAP levels are generally regarded as hallmark of reactive glia, therefore we quantified Gfap transcripts or protein by qPCR or immunostaining, respectively, in different brain areas (cortical, hippocampal, and hypothalamic regions) of control and Bmal1cKO mice at 2 and 4 months after TM treatment.…”

“…Astrocytes have been recently postulated as key contributors to energy balance regulation and obesity due to the discovery of hypothalamic inflammation and gliosis, particularly in the ARC nucleus, in obese rodents and humans (reviewed in McNay, Briançon, Kokoeva, Maratos‐Flier, & Flier, ; Thaler et al, ; Valdearcos, Xu, & Koliwad, ). Remarkably, it was reported that BMAL1 is a potent regulator of astrocyte activation or gliosis (Lananna et al, ; Musiek et al, ). Therefore, we hypothesize that BMAL1 may connect dysregulation of circadian function to hypothalamic astrogliosis leading to the increased body weight and metabolic alteration of Bmal1cKO mice.…”

“…However, the BMAL1 DNA binding is highly rhythmic and regulated by the clock (Koike et al, ), making it difficult to separate entirely from circadian rhythms. For example, the reactive gliosis and astrocyte dysfunction observed in a neuronal‐specific Bmal1KO (Izumo et al, ) or in mice upon circadian disruption by exposure to 10 hr:10 hr light–dark conditions, which blunts BMAL1 oscillations in the brain (Lananna et al, ), suggest that it might be due to the loss of rhythms. On the other hand, it was also reported that arrhythmicity in the setting of increased BMAL1 expression, as in Per1/2 mutant mice, does not induce astrocyte activation (Lananna et al, ).…”

“…For example, the reactive gliosis and astrocyte dysfunction observed in a neuronal‐specific Bmal1KO (Izumo et al, ) or in mice upon circadian disruption by exposure to 10 hr:10 hr light–dark conditions, which blunts BMAL1 oscillations in the brain (Lananna et al, ), suggest that it might be due to the loss of rhythms. On the other hand, it was also reported that arrhythmicity in the setting of increased BMAL1 expression, as in Per1/2 mutant mice, does not induce astrocyte activation (Lananna et al, ). Therefore, it is difficult to discern whether the reactive gliosis is dependent on suppression of BMAL1‐mediated transcription or to the loss of rhythms.…”