Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

Abstract

Bmal1 is an essential component of the molecular clockwork, which drives circadian rhythms in cell function. In Bmal1‐deficient (Bmal1−/−) mice, chronodisruption is associated with cognitive deficits and progressive brain pathology including astrocytosis indicated by increased expression of glial fibrillary acidic protein (GFAP). However, relatively little is known about the impact of Bmal1‐deficiency on astrocyte morphology prior to astrocytosis. Therefore, in this study we analysed astrocyte morphology in young (6–8 weeks old) adult Bmal1−/− mice. At this age, overall GFAP immunoreactivity was not increased in Bmal1‐deficient mice. At the ultrastructural level, we found a decrease in the volume fraction of the fine astrocytic processes that cover the hippocampal mossy fiber synapse, suggesting an impairment of perisynaptic processes and their contribution to neurotransmission. For further analyses of actin cytoskeleton, which is essential for distal process formation, we used cultured Bmal1−/− astrocytes. Bmal1−/− astrocytes showed an impaired formation of actin stress fibers. Moreover, Bmal1−/− astrocytes showed reduced levels of the actin‐binding protein cortactin (CTTN). Cttn promoter region contains an E‐Box like element and chromatin immunoprecipitation revealed that Cttn is a potential Bmal1 target gene. In addition, the level of GTP‐bound (active) Rho‐GTPase (Rho‐GTP) was reduced in Bmal1−/− astrocytes. In summary, our data demonstrate that Bmal1‐deficiency affects morphology of the fine astrocyte processes prior to strong upregulation of GFAP, presumably because of impaired Cttn expression and reduced Rho‐GTP activation. These morphological changes might result in altered synaptic function and, thereby, relate to cognitive deficits in chronodisruption.

The Effects of Light and the Circadian System on Rhythmic Brain Function

“…We have shown that adult neurogenesis is affected in BMAL1-deficient mice [ 59 , 131 , 132 ]. Moreover, the fine astrocytic processes ensheathing the hippocampal mossy fibre synapse and the astrocyte actin cytoskeleton are affected in BMAL1-deficient mice [ 133 ], indicating that the molecular clockwork modulates astrocyte-neuron interaction at the structural level of the tripartite synapse. Consistently, both neurons and astrocytes show time-of-day-dependent structural and functional changes in CA1, while pyramidal neurons change the surface expression of NMDA receptors, and astrocytes change the proximity to synapses [ 80 ].…”

BMAL1 loss in oligodendroglial lineage cells dysregulates myelination and sleep

“…Accumulated levels of PER and CRY within the cytoplasm feed back into the nucleus, displacing the CLOCK and BMAL1 heterodimer and consequently disrupting their own transcription ( 11 ). This transcriptional machinery regulates cytoskeletal factors ( 12 ), cell cycle ( 13 ), and metabolism ( 14 ) in numerous cell populations. OPCs proliferate on a circadian cycle ( 4 ) and sleep deprivation negatively impacts OPC proliferation and differentiation ( 15 ).…”

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

“…In line with this hypothesis, astrocytes of Ophn1 -KO mice are less ramified and show altered migration and glial scar formation [ 326 ]. Moreover, mice deficient for ARNTL (aryl hydrocarbon receptor nuclear translocator like, also known as Bmal1), an essential component of the molecular clockwork driving circadian rhythms, showed severe cognitive deficits, associated with a reduction of perisynaptic astrocytic processes covering hippocampal mossy fiber synapses, which is probably due to a reduction of RHOA activity in Arntl -deficient astrocytes [ 327 ].…”