Loss of STEP61 couples disinhibition to N-methyl-D-aspartate receptor potentiation in rodent and human spinal pain processing
Loss of STEP61 couples disinhibition to N-methyl-D-aspartate receptor potentiation in rodent and human spinal pain processing
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DOI：
10.1093/brain/awz105
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发表时间：
2019-06-01
期刊：
影响因子：
14.5
通讯作者：
Hildebrand, Michael E.
中科院分区：
文献类型：
--
作者：
Dedek, Annemarie;Xu, Jian;Hildebrand, Michael E.
脊髓背角内的兴奋性失调是慢性疼痛的关键介质。在神经病理性疼痛的啮齿动物神经损伤模型中，脑源性神经营养因子介导的抑制丧失(去抑制)阻断了兴奋性GluN2BN-甲基-d-天冬氨酸受体(NMDAR)反应在板层I背角突触的增强。然而，这种机制在疼痛状态和物种中的中心性，以及所涉及的分子连接物，仍然未知。在这里，我们表明，在炎性疼痛的啮齿动物模型中，KCC2依赖的去抑制与GluN2B介导的突触NMDAR反应增加有关，并伴随着酪氨酸磷酸酶STEP61的下调。STEP61活性的降低是启动BDNF随后在I层突触上磷酸化和增强GluN2B NMDAR的必要条件和充分条件。阻断去抑制逆转了STEP61的下调以及炎症介导的行为过敏。我们首次研究了GluN2B介导的人类I层突触的NMDAR反应，并表明一个人体外病理性疼痛处理的BDNF模型下调了KCC2和STEP61，上调了背角突触上的磷酸化GluN2B。我们的结果表明，STEP61是KCC2依赖的去抑制后失去的分子刹车，在啮齿动物和人类病理性疼痛模型中，STEP61活性的降低驱动兴奋性GluN2B NMDAR反应的增强。因此，体外人类BDNF模型可能会在啮齿类动物和人类之间形成一座翻译桥梁，用于识别和验证新的分子疼痛靶点。
Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl-d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP61. The decreased activity of STEP61 is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP61 and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP61 is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP61 activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.