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

Abstract

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.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…This view is supported by experimental evidence in which it was shown that following damage to afferents in the spinal cord, BDNF liberated by microglia activates trkB receptors leading to a KCC2 down-regulation and a depolarizing shift in GABAergic reversal potentials associated with pathological pain responses (Price et al, 2005;Lu et al, 2008). It has also been shown that experimentally induced interictal activity in hippocampal slices maintained in vitro, downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl − extrusion (Rivera et al, 2002(Rivera et al, , 2004Blaesse et al, 2009). Alterations in the balance of NKCC1 and KCC2 activity have also been identified in the subiculum and hippocampus of epileptic patients by Munoz et al (2007).…”

Mesial temporal lobe epilepsy: A pathological replay of developmental mechanisms?

“…This downregulation may be mediated via trk receptors for growth factors whose ambient extracellular concentrations depend on neuronal activity (Rivera et al, 2002). Such a mechanism might operate in human epileptic tissue, but it remains unclear why only a minority of cells are affected.…”

Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn

“…Previous studies in the hippocampus suggested that BDNF mediated KCC2 down-regulation (Rivera et al, 2002;. Consequently, in our study we sought to examine whether increases in BDNF coincided with the decreases in KCC2 levels post-ligation.…”

“…In the adult brain enhanced expression of both BDNF and its high-affinity TrkB receptors appear to predispose certain cortical areas to seizures (Binder et al, 2001). This BDNF-induced hyper-excitability may be at least in part due to the loss of GABA inhibition mediated by the TrkB-dependent down-regulation of KCC2 (Wardle and Poo, 2003;Rivera et al, 2002;.…”