GABAergic regulation of cerebellar NG2-cell development is altered in perinatal white matter injury

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. Oligodendrocyte precursor cells (NG2-cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2-cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABA(A) receptor-mediated synaptic input to NG2-cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABA(A) receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2-cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2-cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI.