Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model

作者全名："Zeng, Xiaoxu; Niu, Yingying; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue"

作者地址："[Zeng, Xiaoxu] Sichuan Univ, West China Univ Hosp 2, Dept Lab Med, Chengdu, Peoples R China; [Zeng, Xiaoxu] Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Childr, Minist Educ, Chengdu, Peoples R China; [Niu, Yingying; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue] Chongqing Med Univ, Affiliated Hosp 1, Lab Res Ctr, Chongqing, Peoples R China"

通信作者："Chen, LX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Lab Res Ctr, Chongqing, Peoples R China."

来源：FRONTIERS IN MOLECULAR NEUROSCIENCE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001004260900001

JCR分区：Q2

影响因子：3.5

年份：2023

卷号：16

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：chronic migraine; inhibitory interneurons; GABABR2; NR2B; synaptic plasticity

摘要："BackgroundAccording to our previous study, the loss of inhibitory interneuron function contributes to central sensitization in chronic migraine (CM). Synaptic plasticity is a vital basis for the occurrence of central sensitization. However, whether the decline in interneuron-mediated inhibition promotes central sensitization by regulating synaptic plasticity in CM remains unclear. Therefore, this study aims to explore the role of interneuron-mediated inhibition in the development of synaptic plasticity in CM. MethodsA CM model was established in rats by repeated dural infusion of inflammatory soup (IS) for 7 days, and the function of inhibitory interneurons was then evaluated. After intraventricular injection of baclofen [a gamma-aminobutyric acid type B receptor (GABABR) agonist] or H89 [a protein kinase A (PKA) inhibitor), behavioral tests were performed. The changes in synaptic plasticity were investigated by determining the levels of the synapse-associated proteins postsynaptic density protein 95 (PSD95), synaptophysin (Syp) and synaptophysin-1(Syt-1)]; evaluating the synaptic ultrastructure by transmission electron microscopy (TEM); and determining the density of synaptic spines via Golgi-Cox staining. Central sensitization was evaluated by measuring calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), c-Fos and substance P (SP) levels. Finally, the PKA/Fyn kinase (Fyn)/tyrosine-phosphorylated NR2B (pNR2B) pathway and downstream calcium-calmodulin-dependent kinase II (CaMKII)/c-AMP-responsive element binding protein (pCREB) signaling were assessed. ResultsWe observed dysfunction of inhibitory interneurons, and found that activation of GABABR ameliorated CM-induced hyperalgesia, repressed the CM-evoked elevation of synapse-associated protein levels and enhancement of synaptic transmission, alleviated the CM-triggered increases in the levels of central sensitization-related proteins, and inhibited CaMKII/pCREB signaling via the PKA/Fyn/pNR2B pathway. The inhibition of PKA suppressed the CM-induced activation of Fyn/pNR2B signaling. ConclusionThese data reveal that the dysfunction of inhibitory interneurons contributes to central sensitization by regulating synaptic plasticity through the GABABR/PKA/Fyn/pNR2B pathway in the periaqueductal gray (PAG) of CM rats. Blockade of GABABR-pNR2B signaling might have a positive influence on the effects of CM therapy by modulating synaptic plasticity in central sensitization."

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