RT Journal Article
SR Electronic
T1 Posttraumatic GABA<sub>A</sub>-Mediated [Ca<sup>2+</sup>]<sub>i</sub> Increase Is Essential for the Induction of Brain-Derived Neurotrophic Factor-Dependent Survival of Mature Central Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6996
OP 7005
DO 10.1523/JNEUROSCI.5268-07.2008
VO 28
IS 27
A1 Anastasia Shulga
A1 Judith Thomas-Crusells
A1 Thomas Sigl
A1 Anne Blaesse
A1 Pedro Mestres
A1 Michael Meyer
A1 Qiao Yan
A1 Kai Kaila
A1 Mart Saarma
A1 Claudio Rivera
A1 Klaus M. Giehl
YR 2008
UL http://www.jneurosci.org/content/28/27/6996.abstract
AB A shift of GABAA-mediated responses from hyperpolarizing to depolarizing after neuronal injury leads to GABAA-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 GABAA-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.