Hypoxia, myelin, and the neonatal brain

Sci. Signal.  05 May 2015:
Vol. 8, Issue 375, pp. ec115
DOI: 10.1126/scisignal.aac4841

Due to impaired respiratory function, premature birth places infants at risk for a neurodevelopmental disorder characterized by a decreased number of the oligodendrocyte precursors NG2 cells and decreased formation of the protective and insulating myelin sheaths that mature oligodendrocytes produce. Zonouzi et al. used mice that expressed a red fluorescent protein in NG2 cells and cells derived from NG2 cells (NG2DsRed mice) to examine the effects of chronic neonatal hypoxia. Analysis of cerebellar sections from newborn mice housed in a hypoxic chamber showed that the cerebellum had reduced size and altered structure. Additionally, the cerebellum had decreased dendritic arborization of Purkinje cells [cerebellar neurons that respond to and release the neurotransmitter γ-aminobutyric acid (GABA)] and decreased abundance of myelin basic protein (MBP). Confocal microscopy for specific markers revealed increased abundance and proliferation of NG2 cells but decreased abundance of mature oligodendrocytes in the cerebellar white matter from neonatal hypoxic NG2DsRed mice compared with controls. However, no difference in marker abundances was observed at postnatal day 60, suggesting hypoxia delayed oligodendrocyte maturation. GABA input evokes inhibitory postsynaptic currents (IPSCs) in NG2 cells, thereby restricting their proliferation and promoting their differentiation. Purkinje cells and interneurons are potential sources of this GABAergic input. Slice recordings and confocal microscopy revealed decreased firing frequency in Purkinje cells and a reduced number of interneurons in hypoxic mice. Whole-cell recordings showed that hypoxia decreased the number of NG2 cells that exhibited spontaneous IPSCs in neonatal mice, although GABAA receptors were still present, indicating that GABAergic input was decreased. In control NG2DsRed mice, the GABAA receptor antagonist bicuculline or N2-specific knockout of the Na+-K+-Cl+ cotransporter NKCC1, which sets the Cl- gradient so that GABA signaling induces depolarization early in development instead of the hyperpolarization that occurs later, increased the number and proliferation of NG2 cells and decreased the number of mature oligodendrocytes. In contrast, pharmacologically increasing the availability of GABA using tiagabine or vigabatrin had the opposite effects, and the GABAA receptor agonist muscimol decreased NG2 cell proliferation. Treating neonatal mice with tiagabine or vigabatrin for several days after hypoxia exposure reversed the effects of hypoxia and increased the abundance of MBP in the cerebellum. The findings suggest that stimulating GABAergic signaling in the neonatal cerebellum may prevent delayed myelination caused by hypoxic conditions.

M. Zonouzi, J. Scafidi, P. Li, B. McEllin, J. Edwards, J. L. Dupree, L. Harvey, D. Sun, C. A. Hübner, S. G. Cull-Candy, M. Farrant, V. Gallo, GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. Nat. Neurosci. 18, 674–682 (2015). [PubMed]

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