Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain
Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain
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DOI：
10.1016/j.neuron.2023.04.010
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发表时间：
2023-07-05
期刊：
影响因子：
16.2
通讯作者：
Tolias, Kimberley F.
中科院分区：
文献类型：
--
作者：
Li, Lingyong;Ru, Qin;Tolias, Kimberley F.
神经性疼痛是一种常见的、使人衰弱的慢性疼痛病症，其由影响躯体感觉神经系统的损伤或疾病引起。了解神经病理性疼痛的病理生理机制对于开发有效治疗慢性疼痛的新治疗策略至关重要。Tiam1是一种Rac1鸟嘌呤核苷酸交换因子（GEF），在海马发育过程中通过诱导肌动蛋白细胞骨架重塑促进树突和突触生长。在这里，使用多种神经性疼痛的动物模型，我们表明，Tiam 1协调突触的结构和功能可塑性在脊髓背角通过肌动蛋白细胞骨架重组和突触NMDAR稳定，这些行动是必不可少的启动，过渡和维持神经性疼痛。此外，靶向脊髓Tiam 1的反义寡核苷酸（ASO）持续减轻神经病理性疼痛敏感性。我们的研究结果表明，Tiam1协调的突触功能和结构可塑性的神经病理性疼痛的病理生理学和Tiam1介导的适应不良的突触可塑性的干预具有长期持久的后果，在神经病理性疼痛管理。
Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the initiation, transition, and maintenance of neuropathic pain. Furthermore, an antisense oligonucleotides (ASO) targeting spinal Tiam1 persistently alleviate neuropathic pain sensitivity. Our findings suggest that Tiam1-coordinated synaptic functional and structural plasticity underlies the pathophysiology of neuropathic pain and that intervention of Tiam1-mediated maladaptive synaptic plasticity has long-lasting consequences in neuropathic pain management.