BDNF-induced TrkB activation down-regulates the K(+)–Cl(−) cotransporter KCC2 and impairs neuronal Cl(−) extrusion

Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl(−) regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K(+)–Cl(− )cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl(−) extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.