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Upregulation of Spinal MDGA1 in Rats After Nerve Injury Alters Interactions Between Neuroligin-2 and Postsynaptic Scaffolding Proteins and Increases GluR1 Subunit Surface Delivery in the Spinal Cord Dorsal Horn

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Abstract

Previous studies suggested that postsynaptic neuroligin-2 may shift from inhibitory toward excitatory function under pathological pain conditions. We hypothesize that nerve injury may increase the expression of spinal MAM-domain GPI-anchored molecule 1 (MDGA1), which can bind to neuroligin-2 and thereby, alter its interactions with postsynaptic scaffolding proteins and increase spinal excitatory synaptic transmission, leading to neuropathic pain. Western blot, immunofluorescence staining, and co-immunoprecipitation studies were conducted to examine the critical role of MDGA1 in the lumbar spinal cord dorsal horn in rats after spinal nerve ligation (SNL). Small interfering ribonucleic acids (siRNAs) targeting MDGA1 were used to examine the functional roles of MDGA1 in neuropathic pain. Protein levels of MDGA1 in the ipsilateral dorsal horn were significantly upregulated at day 7 post-SNL, as compared to that in naïve or sham rats. The increased levels of GluR1 in the synaptosomal membrane fraction of the ipsilateral dorsal horn tissues at day 7 post-SNL was normalized to near sham level by pretreatment with intrathecal MDGA1 siRNA2308, but not scrambled siRNA or vehicle. Notably, knocking down MDGA1 with siRNAs reduced the mechanical and thermal pain hypersensitivities, and inhibited the increased excitatory synaptic interaction between neuroligin-2 with PSD-95, and prevented the decreased inhibitory postsynaptic interactions between neuroligin-2 and Gephyrin. Our findings suggest that SNL upregulated MDGA1 expression in the dorsal horn, which contributes to the pain hypersensitivity through increasing the net excitatory interaction mediated by neuroligin-2 and surface delivery of GluR1 subunit in dorsal horn neurons.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (82171217, 81771181, 81571065), Beijing, China, and the Beijing Natural Science Foundation (7202053), Beijing, China.

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Author notes

  1. Hui-Li Li and Rui-Juan Guo have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, No. 95, Yongan Road, Xicheng District, Beijing, 100050, China

    Hui-Li Li, Rui-Juan Guo & Yun Wang

  2. Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Zhang-Ran Ai

  3. Department of Neurobiology, Capital Medical University, Beijing, 100069, China

    Song Han & Jun-Fa Li

  4. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Yun Guan

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  1. Hui-Li Li
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Contributions

HL: Investigation, writing—original draft, methodology. RJ: Data curation, visualization, investigation. ZR and SH: Data curation, visualization. JF and YG: Conceptualization, methodology, and supervision. YW: Writing—review & editing, supervision, conceptualization.

Corresponding author

Correspondence to Yun Wang.

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Li, HL., Guo, RJ., Ai, ZR. et al. Upregulation of Spinal MDGA1 in Rats After Nerve Injury Alters Interactions Between Neuroligin-2 and Postsynaptic Scaffolding Proteins and Increases GluR1 Subunit Surface Delivery in the Spinal Cord Dorsal Horn. Neurochem Res 49, 507–518 (2024). https://doi.org/10.1007/s11064-023-04049-w

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  • DOI: https://doi.org/10.1007/s11064-023-04049-w

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