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

Marzieh Zonouzi, Joseph Scafidi, Peijun Li, Brian McEllin, Jorge Edwards, Jeffrey L. Dupree, Lloyd Harvey, Dandan Sun, Christian A. Hübner, Stuart G. Cull-Candy*, Mark Farrant, Vittorio Gallo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing 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.

Original languageEnglish
Pages (from-to)674-682
Number of pages9
JournalNature Neuroscience
Volume18
Issue number5
DOIs
StatePublished - 28 Apr 2015
Externally publishedYes

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