title: GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.
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.
authors.affiliation: 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.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Zonouzi
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Scafidi
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Peijun
authors.initials: P
authors.lastname: Li
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: McEllin
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Medical Center, Richmond, Virginia, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dupree
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Harvey
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Friedrich-Schiller-University Jena, Institute of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Cull-Candy
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Farrant
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000473:pathology; D002217:Carbachol / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D002531:Cerebellum / Q000254:growth & development / Q000473:pathology*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000633:toxicity; D002534:Hypoxia, Brain / Q000473:pathology / Q000503:physiopathology*; D007395:Interneurons / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology / Q000627:therapeutic use; D009836:Oligodendroglia / Q000166:cytology*; D011689:Purkinje Cells / Q000473:pathology; D011963:Receptors, GABA-A / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2 / Q000172:deficiency / Q000502:physiology; D000078308:Tiagabine; D020888:Vigabatrin / Q000494:pharmacology / Q000627:therapeutic use; D066127:White Matter / Q000293:injuries*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D058787:GABA-A Receptor Antagonists; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C578878:Slc12a2 protein, mouse; D064506:Solute Carrier Family 12, Member 2; D005680:gamma-Aminobutyric Acid; D002217:Carbachol; D020888:Vigabatrin; D000078308:Tiagabine
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