Format

Send to

Choose Destination
Nat Neurosci. 2015 May;18(5):674-82. doi: 10.1038/nn.3990. Epub 2015 Mar 30.

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

Author information

1
1] Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. [2] Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
2
1] Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. [2] Department of Neurology, Children's National Medical Center, Washington, DC, USA.
3
Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
4
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Medical Center, Richmond, Virginia, USA.
5
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
6
Friedrich-Schiller-University Jena, Institute of Human Genetics, Jena University Hospital, Jena, Germany.
7
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

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 GABAA 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 GABAA 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.

PMID:
25821912
PMCID:
PMC4459267
DOI:
10.1038/nn.3990
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center