Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model
Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model
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DOI：
10.1016/j.neuron.2004.06.019
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发表时间：
2004-07-08
期刊：
影响因子：
16.2
通讯作者：
McNamara, JO
中科院分区：
文献类型：
--
作者：
He, XP;Kotloski, R;McNamara, JO
癫痫发生是一个正常的大脑成为癫痫的过程。我们假设神经营养因子脑源性神经营养因子（BDNF）激活其受体，TrkB，在海马癫痫发生过程中，BDNF介导的激活TrkB是癫痫发生所必需的。我们使用点燃模型在Synapsin-Cre条件性BDNF-/-和TrkB（-/-）小鼠中测试了这些假设。尽管BDNF表达显著降低，但在BDNF-/-小鼠中仅检测到癫痫发生的适度损害和海马TrkB活化增加。相比之下，在TrkB（-/-）小鼠中检测到电生理测量的减少和癫痫发生的行为证据。重要的是，TrkB（-/-）小鼠表现出癫痫发生、强直-阵挛性癫痫发作的行为终点。然而，TrkB可以被激活，并且在BDNF-/-小鼠中癫痫发生发展，而在TrkB（-/-）小鼠中癫痫发生的可塑性被消除。其在点燃中对癫痫发生的需求暗示TrkB和下游信号传导途径是预防癫痫药物的有吸引力的分子靶点。
Epileptogenesis is the process whereby a normal brain becomes epileptic. We hypothesized that the neurotrophin brain-derived neurotrophic factor (BDNF) activates its receptor, TrkB, in the hippocampus during epileptogenesis and that BDNF-mediated activation of TrkB is required for epileptogenesis. We tested these hypotheses in Synapsin-Cre conditional BDNF-/- and TrkB(-/-) mice using the kindling model. Despite marked reductions of BDNF expression, only a modest impairment of epileptogenesis and increased hippocampal TrkB activation were detected in BDNF-/- mice. In contrast, reductions of electrophysiological measures and no behavioral evidence of epileptogenesis were detected in TrkB(-/-) mice. Importantly, TrkB(-/-) mice exhibited behavioral endpoints of epileptogenesis, tonic-clonic seizures. Whereas TrkB can be activated, and epileptogenesis develops in BDNF-/- mice, the plasticity of epileptogenesis is eliminated in TrkB(-/-) mice. Its requirement for epileptogenesis in kindling implicates TrkB and downstream signaling pathways as attractive molecular targets for drugs for preventing epilepsy.