Pain symptoms can be transmitted across generations, but the mechanisms underlying these outcomes remain poorly understood. Here, we identified an essential role for primary somatosensory cortical (S1) glutamate neuronal DNA methyl-CpG binding protein 2 (MeCP2) in the transgenerational transmission of pain. In a female mouse chronic pain model, the offspring displayed significant pain sensitization. In these mice, MeCP2 expression was increased in S1 glutamate (GluS1) neurons, correlating with increased neuronal activity. Downregulation of GluS1 neuronal MeCP2 in maternal mice with pain abolished offspring pain sensitization, whereas overexpression of MeCP2 in naïve maternal mice induced pain sensitization in offspring. Notably, single-cell sequencing and chromatin immunoprecipitation analysis showed that the expression of a wide range of genes was changed in offspring and maternal GluS1 neurons, some of which were regulated by MeCP2. These results collectively demonstrate the putative importance of MeCP2 as a key regulator in pain transgenerational transmission through actions on GluS1 neuronal maladaptation.

中文翻译：

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MeCP2 介导慢性疼痛的跨代传递。

疼痛症状可以跨代传播，但这些结果背后的机制仍然知之甚少。在这里，我们确定了初级体感皮层 (S1) 谷氨酸神经元 DNA 甲基-CpG 结合蛋白 2 (MeCP2) 在疼痛的跨代传递中的重要作用。在雌性小鼠慢性疼痛模型中，后代表现出显着的疼痛敏感性。在这些小鼠中，S1 谷氨酸 (GluS1) 神经元中的 MeCP2 表达增加，与神经元活动增加相关。在有疼痛的母鼠中下调 GluS1 神经元 MeCP2 消除了后代的疼痛敏化，而在幼稚的母鼠中过度表达 MeCP2 会诱导后代的疼痛敏化。尤其，单细胞测序和染色质免疫沉淀分析表明，后代和母体 GluS1 神经元中广泛基因的表达发生了变化，其中一些受 MeCP2 调控。这些结果共同证明了 MeCP2 作为疼痛跨代传递的关键调节剂的推定重要性，通过对 GluS1 神经元适应不良的作用。