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

Abstract

Complex neurodevelopmental disorders involve motor as well as cognitive dysfunction and these impairments are associated with both cerebral and cerebellar maturity. A network of connections between these two brain regions is proposed to underlie neurodevelopmental impairments. The cerebellar gray matter has a protracted developmental timeline compared to the cerebral cortex, however, making the association of these relay pathways unclear for neurodevelopmental disabilities. We show that a population of amoeboid microglia infiltrate the cerebellar white matter through the fourth ventricular zone during early postnatal development. This infiltration is synchronized with the emergence of amoeboid microglia in the ventricular zone of the lateral ventricles and appearance in cerebral white matter. Amoeboid microglia phagocytosed oligodendrocyte progenitor cells (OPCs) in the cerebellar white matter during a restricted early postnatal time window before transitioning to a ramified morphology. Modulating fractalkine receptor signaling, shown to be involved in microglial pruning of synapses, significantly reduced microglial engulfment of OPCs resulting in increased numbers of OLs and altered myelin formation. Variants in the fractalkine receptor are associated with neurodevelopmental disorders including schizophrenia and autism where myelin perturbations have been documented. Overall, these data support that white matter refinement by amoeboid microglia is coordinated in both cerebral and cerebellar development with important implications for altered circuit function in neurodevelopmental disabilities. One sentence summaryMicroglia engulf oligodendrocyte progenitors in the developing cerebellum