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The Journal of Neuroscience, February 13, 2008, 28(7):1588-1597; doi:10.1523/JNEUROSCI.3791-07.2008

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Development/Plasticity/Repair
Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

Annie Reynolds,^1,2,3 Edna Brustein,^1,2 Meijiang Liao,^1,2 Adriana Mercado,⁵ Elisa Babilonia,⁵ David B. Mount,^5,6 and Pierre Drapeau^1,2,3,4

¹Department of Pathology and Cell Biology and Le Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada H3T 1J4, ²Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1A4, ³Department of Biology, McGill University, Montréal, Québec, Canada H3A 1B1, ⁴Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada H3A 2B4, ⁵Renal Division, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, and ⁶Division of General Internal Medicine, Veterans Affairs Boston Healthcare System, Harvard Medical School, West Roxbury, Massachusetts 02132

Correspondence should be addressed to Pierre Drapeau, Department of Pathology and Cell Biology, Université de Montréal, Pavillon Roger-Gaudry N-535, 2900, Boulevard Édouard-Montpetit, Montréal, Québec, Canada H3T 1J4. Email: p.drapeau{at}umontreal.ca

GABA- and glycine-induced depolarization is thought to provide important developmental signals, but the role of the underlying chloride gradient has not been examined from the onset of development. We therefore overexpressed globally the potassium–chloride cotransporter 2 (KCC2) in newly fertilized zebrafish embryos to reverse the chloride gradient. This rendered glycine hyperpolarizing in all neurons, tested at the time that motor behaviors (but not native KCC2) first appear. KCC2 overexpression resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity. We observed fewer motoneurons and interneurons, a reduction in the elaboration of axonal tracts, and smaller brains and spinal cords. However, we observed no increased apoptosis and a normal complement of sensory neurons, glia, and progenitors. These results suggest that chloride-mediated excitation plays a crucial role in promoting neurogenesis from the earliest stages of embryonic development.

Key words: differentiation; axonal growth; zebrafish; cotransporter; neuronal excitability; glycine

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Received Aug. 20, 2007; revised Nov. 30, 2007; accepted Dec. 29, 2007.

Correspondence should be addressed to Pierre Drapeau, Department of Pathology and Cell Biology, Université de Montréal, Pavillon Roger-Gaudry N-535, 2900, Boulevard Édouard-Montpetit, Montréal, Québec, Canada H3T 1J4. Email: p.drapeau{at}umontreal.ca

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