Cerebellar white matter development is regulated by fractalkine-dependent microglia phagocytosis of oligodendrocyte progenitor cells

Neurodevelopmental disorders often involve both motor and cognitive impairments, linked to the maturation of cerebral and cerebellar regions. This study reveals that during early postnatal development, ameboid microglia infiltrate the cerebellar white matter via the fourth ventricular zone, in parallel with similar activity in the cerebral white matter. These microglia phagocytose oligodendrocyte progenitor cells (OPCs) within a restricted time window before transitioning to a ramified state. The disruption of fractalkine receptor signaling-known to mediate synaptic pruning-reduces microglial OPC engulfment, leading to an increase in oligodendrocytes and altered myelin development. Variants in the fractalkine receptor gene have been linked to neurodevelopmental disorders such as autism and schizophrenia, both of which involve myelin abnormalities. These findings highlight a coordinated role of ameboid microglia in shaping white matter development in both the cerebrum and cerebellum, suggesting that disruptions in this process may contribute to altered brain circuitry and function in neurodevelopmental disorders.