Restoration of Cingulate Long-Term Depression by Enhancing Non-apoptotic Caspase 3 Alleviates Peripheral Pain Hypersensitivity

• Published in: Cell Reports Vol. 33; no. 6; p. 108369
• Main Authors: Wang, Yong-Jie, Liu, Ming-Gang, Wang, Jing-Hua, Cao, Wei, Wu, Cheng, Wang, Zi-Yue, Liu, Li, Yang, Fan, Feng, Zhi-Hui, Sun, Li, Zhang, Fuxing, Shen, Yi, Zhou, Yu-Dong, Zhuo, Min, Luo, Jian-Hong, Xu, Tian-Le, Li, Xiang-Yao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.11.2020; Elsevier BV
• Subjects: Casp3 and GluA1 interaction; Caspase 3; Depression; GluA1 internalization; GluA2; Gyrus Cinguli; Humans; hypersensitivity; LTD; Neuralgia; neuropathic pain; non-apoptotic function; spontaneous pain; synaptic transmission; neuropathic pain; hypersensitivity; Casp3 and GluA1 interaction; spontaneous pain; synaptic transmission; GluA2; caspase 3; LTD; GluA1 internalization; non-apoptotic function
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108369

Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of ∼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management. [Display omitted] •Peripheral nerve injury suppresses LTD and downregulates Casp3 in the ACC•Amino acid sequence (QGCDISP) in AMPAR subunits is identified as a Casp3 binding site•Decreasing cingulate Casp3 suppresses LTD and induces peripheral hypersensitivity•Overexpression of cingulate Casp3 reduces peripheral pain hypersensitivity Wang et al. find that peripheral nerve injury prevents LTD induction in the anterior cingulate cortex (ACC) due to the downregulation of Casp3. Disrupting the interaction between Casp3 and AMPAR subunits inhibits LTD induction and induces peripheral pain hypersensitivity. Restoration of cingulate LTD rescues peripheral pain hypersensitivity.