Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony
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Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is believed to be a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling, from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein and histological analyses. We identified a delayed microglial response coupling interferon signaling to mitotic progression, and a subsequent induction of temporally regulated subtypes. IR rewired the parenchymal phagocyte profiles due to progressive microglial loss, failure of repopulation through self-renewal and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were confirmed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with synaptic aberrant regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid tailoring therapies to preserve cognition in cancer survivors.
