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The Journal of Neuroscience, July 2, 2008, 28(27):6996-7005; doi:10.1523/JNEUROSCI.5268-07.2008

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Development/Plasticity/Repair
Posttraumatic GABA_A-Mediated [Ca²⁺]_i Increase Is Essential for the Induction of Brain-Derived Neurotrophic Factor-Dependent Survival of Mature Central Neurons

Anastasia Shulga,^1 * Judith Thomas-Crusells,^1 * Thomas Sigl,⁴ Anne Blaesse,¹ Pedro Mestres,⁴ Michael Meyer,⁵ Qiao Yan,⁶ Kai Kaila,^2,3 Mart Saarma,¹ Claudio Rivera,¹ and Klaus M. Giehl^4,7

¹Institute of Biotechnology, ²Department of Biological and Environmental Sciences, and ³Neuroscience Center, University of Helsinki, FIN-00014 Helsinki, Finland, ⁴Department of Anatomy and Cell Biology, University of Saarland, 66421 Homburg, Germany, ⁵Physiologisches Institut, Ludwigs-Maximilians Universität München, 80336 Münich, Germany, ⁶Amgen, Inc., Thousand Oaks, California 91320-1799, and ⁷Center for Molecular Neuroscience, The Ohio State University, Columbus, Ohio 43210

Correspondence should be addressed to either of the following: Dr. Claudio Rivera, Group Leader, Senior Research Fellow of the Academy of Finland, Institute of Biotechnology, University of Helsinki, Viikki Biocenter, Viikinkaari 9, FIN-00014 Helsinki, Finland, Email: claudio.rivera{at}helsinki.fi; or Dr. Klaus M. Giehl, Center for Molecular Neuroscience, The Ohio State University, Columbus, OH 43210, Email: klausgiehl{at}gmx.de

A shift of GABA_A-mediated responses from hyperpolarizing to depolarizing after neuronal injury leads to GABA_A-mediated increase in [Ca²⁺]_i. In addition, central neurons become dependent on BDNF for survival. Whether these two mechanisms are causally interrelated is an open question. Here, we show in lesioned CA3 hippocampal neurons in vitro and in axotomized corticospinal neurons in vivo that posttraumatic downregulation of the neuron-specific K–Cl cotransporter KCC2 leads to intracellular chloride accumulation by the Na–K–2Cl cotransporter NKCC1, resulting in GABA-induced [Ca²⁺]_i transients. This mechanism is required by a population of neurons to survive in a BDNF-dependent manner after injury, because blocking GABA_A-depolarization with the NKCC1 inhibitor bumetanide prevents the loss of neurons on BDNF withdrawal. The resurgence of KCC2 expression during recovery coincides with loss of BDNF dependency for survival. This is likely mediated through BDNF itself, because injured neurons reverse their response to this neurotrophin by switching the BDNF-induced downregulation of KCC2 to upregulation.

Key words: chloride homeostasis; intracellular Ca²⁺; trophic factors; neuronal survival; KCC2; NKCC1

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Received May 28, 2007; revised May 7, 2008; accepted May 23, 2008.

Correspondence should be addressed to either of the following: Dr. Claudio Rivera, Group Leader, Senior Research Fellow of the Academy of Finland, Institute of Biotechnology, University of Helsinki, Viikki Biocenter, Viikinkaari 9, FIN-00014 Helsinki, Finland, Email: claudio.rivera{at}helsinki.fi; or Dr. Klaus M. Giehl, Center for Molecular Neuroscience, The Ohio State University, Columbus, OH 43210, Email: klausgiehl{at}gmx.de

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