Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing
Potentiation of Synaptic GluN2B NMDAR Currents by Fyn Kinase Is Gated through BDNF-Mediated Disinhibition in Spinal Pain Processing
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DOI：
10.1016/j.celrep.2016.11.024
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发表时间：
2016-12-06
期刊：
影响因子：
8.8
通讯作者：
Salter, Michael W.
中科院分区：
文献类型：
--
作者：
Hildebrand, Michael E.;Xu, Jian;Salter, Michael W.
在慢性疼痛状态下，神经营养因子脑源性神经营养因子(BDNF)通过减少突触抑制来改变I层脊髓神经元的输出。疼痛超敏也依赖于N-甲基-D-天冬氨酸受体(NMDAR)和Src家族激酶，但NMDAR失调的部位尚不清楚。在这里，我们展示了在神经病理性疼痛的外周神经损伤模型中，NMDAR介导的突触I层电流被增强。我们发现，BDNF通过激活TrkB和通过Src家族激酶Fyn磷酸化GluN2B亚基来介导NMDAR的增强。令人惊讶的是，我们发现依赖于氯的去抑制是必要的，也是充分的，以启动BDNF对突触NMDAR的增强。因此，我们认为脊髓痛的放大是由一种前馈机制介导的，通过失去抑制来抑制单个I层神经元内突触兴奋的增加。鉴于单独解除抑制和BDNF-TrkB信号都不足以增强NMDARs，我们在I层神经元中发现了一种形式的分子符合检测。
In chronic pain states, the neurotrophin brain-derived neurotrophic factor (BDNF) transforms the output of lamina I spinal neurons by decreasing synaptic inhibition. Pain hypersensitivity also depends on N-methyl-D-aspartate receptors (NMDARs) and Src-family kinases, but the locus of NMDAR dysregulation remains unknown. Here, we show that NMDAR-mediated currents at lamina I synapses are potentiated in a peripheral nerve injury model of neuropathic pain. We find that BDNF mediates NMDAR potentiation through activation of TrkB and phosphorylation of the GluN2B subunit by the Src-family kinase Fyn. Surprisingly, we find that Cl--dependent disinhibition is necessary and sufficient to prime potentiation of synaptic NMDARs by BDNF. Thus, we propose that spinal pain amplification is mediated by a feedforward mechanism whereby loss of inhibition gates the increase in synaptic excitation within individual lamina I neurons. Given that neither disinhibition alone nor BDNF-TrkB signaling is sufficient to potentiate NMDARs, we have discovered a form of molecular coincidence detection in lamina I neurons.