Spinal astrocytic MeCP2 regulates Kir4.1 for the maintenance of chronic hyperalgesia in neuropathic pain
Spinal astrocytic MeCP2 regulates Kir4.1 for the maintenance of chronic hyperalgesia in neuropathic pain
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DOI：
10.1016/j.pneurobio.2023.102436
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发表时间：
2023-03
影响因子：
6.7
通讯作者：
M. Ou;Yali Chen;Jin Liu;Donghang Zhang;Yaoxin Yang;Jie-Fei Shen;C. Miao;Shao-Jun Tang;Xin Liu;D. Mulkey;Tao Zhu;Cheng Zhou
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文献类型：
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作者：
M. Ou;Yali Chen;Jin Liu;Donghang Zhang;Yaoxin Yang;Jie-Fei Shen;C. Miao;Shao-Jun Tang;Xin Liu;D. Mulkey;Tao Zhu;Cheng Zhou
脊髓背角星形胶质细胞的激活可能在慢性神经病理性疼痛的发生发展中起重要作用，但星形胶质细胞激活及其调节作用的机制尚不清楚。内向整流钾通道蛋白4.1（Kir4.1）是星形胶质细胞中最重要的背景钾通道。然而，Kir4.1是如何调节和促进慢性疼痛中的行为痛觉过敏的尚不清楚。在这项研究中，单细胞RNA测序分析表明，Kir4.1和甲基-CpG-结合蛋白2（MeCP 2）的表达水平降低脊髓星形胶质细胞在慢性压迫性损伤（CCI）的小鼠模型。条件性敲除脊髓星形胶质细胞Kir4.1通道可导致痛觉过敏，而脊髓Kir4.1通道过表达可减轻CCI诱导的痛觉过敏。CCI后脊髓Kir4.1的表达受MeCP 2的调节。脊髓切片电生理记录显示，敲低Kir4.1可显著上调星形胶质细胞的兴奋性，进而改变脊髓背角神经元的放电模式。因此，靶向脊髓Kir4.1可能是慢性神经病理性疼痛中痛觉过敏的治疗方法。
Astrocyte activation in the spinal dorsal horn may play an important role in the development of chronic neuropathic pain, but the mechanisms involved in astrocyte activation and their modulatory effects remain unknown. The inward rectifying potassium channel protein 4.1 (Kir4.1) is the most important background K+channel in astrocytes. However, how Kir4.1 is regulated and contributes to behavioral hyperalgesia in chronic pain is unknown. In this study, single-cell RNA sequencing analysis indicated that the expression levels of both Kir4.1 and Methyl-CpG-binding protein 2 (MeCP2) were decreased in spinal astrocytes after chronic constriction injury (CCI) in a mouse model. Conditional knockout of the Kir4.1 channel in spinal astrocytes led to hyperalgesia, and overexpression of the Kir4.1 channel in spinal cord relieved CCI-induced hyperalgesia. Expression of spinal Kir4.1 after CCI was regulated by MeCP2. Electrophysiological recording in spinal slices showed that knockdown of Kir4.1 significantly up-regulated the excitability of astrocytes and then functionally changed the firing patterns of neurons in dorsal spinal cord. Therefore, targeting spinal Kir4.1 may be a therapeutic approach for hyperalgesia in chronic neuropathic pain.