BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion.
BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion.
复制标题
BDNF诱导的TRKB激活下调K+-cl- cotransporter KCC2并损害神经元CL-挤出。
DOI：
10.1083/jcb.200209011
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发表时间：
2002-12-09
影响因子：
7.8
通讯作者：
Saarma, Mart
中科院分区：
文献类型：
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作者：
Rivera, Claudio;Li, Hong;Thomas-Crusells, Judith;Lahtinen, Hannele;Viitanen, Tero;Nanobashvili, Avtandil;Kokaia, Zaal;Airaksinen, Matti S;Voipio, Juha;Kaila, Kai;Saarma, Mart
已知病理生理活动和各种创伤性损伤对神经元Cl−调节具有有害的长期影响，可导致快速突触后GABA能反应受到抑制。脑源性神经营养因子（BDNF）通过多种机制增加神经元兴奋性，包括调节GABA能传递的功效。在这里，我们发现，大鼠海马脑片培养物和急性脑片暴露于外源性BDNF或神经营养因子-4导致TrkB介导的神经元特异性K+-Cl−协同转运蛋白KCC 2 mRNA和蛋白质的下降，以及神经元Cl−挤出能力的损害。在点燃诱导的癫痫发作后，KCC 2的表达在小鼠海马中下调，其时空分布与TrkB和BDNF的上调互补。目前的数据证明了一种新的机制，BDNF/TrkB信号抑制氯依赖性快速GABA能抑制，这最有可能有助于众所周知的作用，TrkB激活的信号级联在诱导和建立癫痫活动。
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.