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Peer-reviewedCC BYCommunications Biology

OGT-mediated PIN O-GlcNAcylation drives depression-like behaviors by impairing NOS-stargazin-GluA1 signaling

  • Xunhu Gu1
  • Xu Liu1
  • Yong Xiong2
  • Xuefen Chen1
  • Yancai Zhang1
  • Li-Li Zheng3
  • Wei Wang1
  1. 1Department of Neurology, The Second Affiliated Hospital of Nanchang University
  2. 2Department of Neurology, Xinjian District People’s Hospital
  3. 3Department of Pharmacy, Jiangxi Maternal and Child Health Hospital
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Abstract

Major depressive disorder is associated with impaired excitatory synaptic transmission, but the molecular mechanisms linking chronic stress to altered AMPA receptor trafficking remain incompletely understood. Here we show that chronic mild stress increases OGT-mediated O-GlcNAcylation of PIN at serine 88, which stabilizes PIN and enhances its interaction with nitric oxide synthase. This suppresses nitric oxide synthase activity, reduces stargazin S-nitrosylation, weakens stargazin-GluA1 binding, and impairs GluA1-containing AMPA receptor trafficking. Genetic or pharmacological inhibition of OGT restores this signaling pathway and alleviates stress-induced depression-like behaviors in mice. These findings identify the OGT-PIN-NOS-stargazin axis as a regulator of stress-induced synaptic dysfunction and suggest that targeting OGT may help restore AMPA receptor trafficking in depression-related conditions.

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Cite

BibTeXRIS
BibTeX
@article{gu2026ogtmediated,
  title = {{OGT-mediated PIN O-GlcNAcylation drives depression-like behaviors by impairing NOS-stargazin-GluA1 signaling}},
  author = {Xunhu Gu and Xu Liu and Yong Xiong and Xuefen Chen and Yancai Zhang and Li-Li Zheng and Wei Wang},
  journal = {Communications Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s42003-026-10423-5},
  url = {https://doi.org/10.1038/s42003-026-10423-5},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - OGT-mediated PIN O-GlcNAcylation drives depression-like behaviors by impairing NOS-stargazin-GluA1 signaling
AU  - Xunhu Gu
AU  - Xu Liu
AU  - Yong Xiong
AU  - Xuefen Chen
AU  - Yancai Zhang
AU  - Li-Li Zheng
AU  - Wei Wang
PY  - 2026
DA  - 2026/06/01
JO  - Communications Biology
DO  - 10.1038/s42003-026-10423-5
UR  - https://doi.org/10.1038/s42003-026-10423-5
AB  - Major depressive disorder is associated with impaired excitatory synaptic transmission, but the molecular mechanisms linking chronic stress to altered AMPA receptor trafficking remain incompletely understood. Here we show that chronic mild stress increases OGT-mediated O-GlcNAcylation of PIN at serine 88, which stabilizes PIN and enhances its interaction with nitric oxide synthase. This suppresses nitric oxide synthase activity, reduces stargazin S-nitrosylation, weakens stargazin-GluA1 binding, and impairs GluA1-containing AMPA receptor trafficking. Genetic or pharmacological inhibition of OGT restores this signaling pathway and alleviates stress-induced depression-like behaviors in mice. These findings identify the OGT-PIN-NOS-stargazin axis as a regulator of stress-induced synaptic dysfunction and suggest that targeting OGT may help restore AMPA receptor trafficking in depression-related conditions.
SN  - 2399-3642
ER  -