title: Posttraumatic GABA(A)-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons.
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.
authors.affiliation: Institute of Biotechnology, Department of Biological and Environmental Sciences, and Neuroscience Center, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Shulga
authors.forename: Judith
authors.initials: J
authors.lastname: Thomas-Crusells
authors.forename: Thomas
authors.initials: T
authors.lastname: Sigl
authors.forename: Anne
authors.initials: A
authors.lastname: Blaesse
authors.forename: Pedro
authors.initials: P
authors.lastname: Mestres
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Qiao
authors.initials: Q
authors.lastname: Yan
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Giehl
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology; D019771:Axotomy; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002034:Bumetanide / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D011712:Pyramidal Tracts / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002034:Bumetanide; D002712:Chlorides; D011963:Receptors, GABA-A; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse; C578879:Slc12a2 protein, rat