HYPOXIA DISRUPTS THE CIRCADIAN CLOCK IN ASTROCYTES AND INDUCES SYNAPSE PHAGOCYTOSIS DEFECTS

Perinatal hypoxia is a leading environmental risk factor for neurodevelopmental diseases which exhibit both synapse function defects and circadian disruptions. Here, we investigated the effects of hypoxia on astrocytes, a cell type that is being increasingly recognized as key regulator of synaptic network maturation and function through synapse phagocytosis. Using human cortical organoids (hCO) derived from induced pluripotent stem cells (hiPSCs), we identified that hypoxia significantly inhibits synapse phagocytosis by astrocytes, and that this phenotype is mediated through disruptions in the astrocytic circadian clock genes and subsequent decreased expression of MEGF10. Importantly, we also demonstrated that circadian clock disruptions are sufficient to induce synaptic phagocytosis phenotypes even in the absence of hypoxia, and validated these findings in mouse models.
Overall, we uncovered a novel mechanistic link between hypoxia, circadian disruptions and synapse pruning by astrocytes, as contributing factors to the development of neuropsychiatric diseases following a perinatal hypoxic event. Separately, we demonstrate the presence of circadian rhythms in hCOs, thus opening an unprecedented opportunity to dissect the role of circadian clocks in normal brain development and how it contributes to specific diseases of environmental or genetic origin.