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

doi:10.1038/nn.3990

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

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

Authors

Affiliations

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.

PMID: 25821912
PMCID: PMC4459267
DOI: 10.1038/nn.3990

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Animals
Animals, Newborn
Asphyxia Neonatorum / pathology
Carbachol / pharmacology
Cell Count
Cells, Cultured
Cerebellum / growth & development
Cerebellum / pathology*
Demyelinating Diseases / chemically induced
Demyelinating Diseases / etiology*
Disease Models, Animal
Female
GABA-A Receptor Antagonists / toxicity
Hypoxia, Brain / pathology
Hypoxia, Brain / physiopathology*
Interneurons / pathology
Male
Mice
Mice, Knockout
Mice, Transgenic
Neural Stem Cells / cytology*
Neurogenesis / drug effects
Neurogenesis / physiology*
Nipecotic Acids / pharmacology
Nipecotic Acids / therapeutic use
Oligodendroglia / cytology*
Purkinje Cells / pathology
Receptors, GABA-A / physiology*
Solute Carrier Family 12, Member 2 / deficiency
Solute Carrier Family 12, Member 2 / physiology
Tiagabine
Vigabatrin / pharmacology
Vigabatrin / therapeutic use
White Matter / injuries*
gamma-Aminobutyric Acid / physiology*

Substances

GABA-A Receptor Antagonists
Nipecotic Acids
Receptors, GABA-A
Slc12a2 protein, mouse
Solute Carrier Family 12, Member 2
gamma-Aminobutyric Acid
Carbachol
Vigabatrin
Tiagabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding