Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction

Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of alpha V beta 8 from the central nervous system (Itgb8 Delta CNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These dysmature microglia appear to result from reduced TGF beta signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGF beta signaling during adulthood, and directly cause a unique neurodevelopmental syndrome characterized by oligodendrocyte maturational arrest, interneuron loss, and spastic neuromotor dysfunction. Consistent with this, early (but not late) microglia depletion completely reverses this phenotype. Together, these data identify novel roles for alpha V beta 8 and TGF beta signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.