Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Axons / metabolism
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Axons / pathology
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Axotomy
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Brain Injuries / metabolism*
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Brain Injuries / physiopathology
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Brain-Derived Neurotrophic Factor / metabolism*
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Bumetanide / pharmacology
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cell Survival / drug effects
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Cell Survival / physiology
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Chlorides / metabolism
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Hippocampus / metabolism
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Hippocampus / physiopathology
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K Cl- Cotransporters
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Mice
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Nerve Regeneration / drug effects
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Nerve Regeneration / physiology*
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Neural Inhibition / drug effects
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Neural Inhibition / physiology
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Neurons / drug effects
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Neurons / metabolism*
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Organ Culture Techniques
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Pyramidal Tracts / metabolism
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Pyramidal Tracts / physiopathology
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Rats
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Rats, Sprague-Dawley
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Receptors, GABA-A / drug effects
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Receptors, GABA-A / metabolism*
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Sodium Potassium Chloride Symporter Inhibitors
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Sodium-Potassium-Chloride Symporters / metabolism
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Solute Carrier Family 12, Member 2
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Symporters / metabolism*
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gamma-Aminobutyric Acid / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Chlorides
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Receptors, GABA-A
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Slc12a2 protein, mouse
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Slc12a2 protein, rat
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Sodium Potassium Chloride Symporter Inhibitors
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Sodium-Potassium-Chloride Symporters
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Solute Carrier Family 12, Member 2
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Symporters
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Bumetanide
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gamma-Aminobutyric Acid