Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model
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 prom...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1142072/full |
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| author | Xiaoxu Zeng Xiaoxu Zeng Yingying Niu Guangcheng Qin Dunke Zhang Lixue Chen |
| author_facet | Xiaoxu Zeng Xiaoxu Zeng Yingying Niu Guangcheng Qin Dunke Zhang Lixue Chen |
| author_sort | Xiaoxu Zeng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T08:21:27Z |
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| language | English |
| last_indexed | 2024-03-13T08:21:27Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-29daba9e4baf466baa1a2ec010a069db2023-05-31T08:40:47ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-05-011610.3389/fnmol.2023.11420721142072Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat modelXiaoxu Zeng0Xiaoxu Zeng1Yingying Niu2Guangcheng Qin3Dunke Zhang4Lixue Chen5Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, ChinaLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaBackgroundAccording 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.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1142072/fullchronic migraineinhibitory interneuronsGABABR2NR2Bsynaptic plasticity |
| spellingShingle | Xiaoxu Zeng Xiaoxu Zeng Yingying Niu Guangcheng Qin Dunke Zhang Lixue Chen Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model Frontiers in Molecular Neuroscience chronic migraine inhibitory interneurons GABABR2 NR2B synaptic plasticity |
| title | Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model |
| title_full | Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model |
| title_fullStr | Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model |
| title_full_unstemmed | Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model |
| title_short | Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model |
| title_sort | dysfunction of inhibitory interneurons contributes to synaptic plasticity via gababr pnr2b signaling in a chronic migraine rat model |
| topic | chronic migraine inhibitory interneurons GABABR2 NR2B synaptic plasticity |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1142072/full |
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