2. Academic Validation
  3. SARS-CoV-2 spike protein induces depressive-like behaviors by disrupting astrocytic Cx43-mediated gap junction intercellular communication

SARS-CoV-2 spike protein induces depressive-like behaviors by disrupting astrocytic Cx43-mediated gap junction intercellular communication

  • Brain Behav Immun. 2026 Jan:131:106176. doi: 10.1016/j.bbi.2025.106176.
Ruo-Lan Yuan 1,  Sha-Sha Wang 2,  Pei-Yi Li 1,  Yuan Ruan 1,  Jia-Qi He 1,  Run Zhou 3,  Wen-Fei Wang 4,  Yu-Tong Jiang 1,  Jun-Rui Ye 3,  Ye Peng 5,  Wen-Bin He 6,  Shi-Feng Chu 7,  Zhao Zhang 8,  Nai-Hong Chen 9
Affiliations

Affiliations

  • 1 Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
  • 2 Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 4 Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
  • 6 National International Joint Research Center for Molecular Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan 030619, China.
  • 7 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 9 Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China. Electronic address: [email protected].
PMID: 41238086 DOI: 10.1016/j.bbi.2025.106176
Abstract

Background: Long COVID has emerged as a global health concern, with depression being one of its most debilitating and poorly understood manifestations. Despite evidence pointing to the role of neuroinflammation and astrocyte-mediated disruptions in brain function, the mechanistic details remain elusive.

Methods: SARS-CoV-2 spike receptor-binding domain (RBD) was microinjected into the medial prefrontal cortex (mPFC) to mimic cerebral Infection, and the depressive-like behaviors, functional connectivity, and neuronal excitability were recorded for a 16-day period. Immunofluorescence, RNA Sequencing, and ELISA were used to evaluate astrocytic gap junctions and inflammation. Gap junction intercellular communication (GJIC) dysfunction was confirmed by transfer of lucifer yellow (LY), cyclic adenosine monophosphate (cAMP), and cyclic GMP-AMP (cGAMP). We also investigated the role of Cx43 using conditional knockout mice, Gap 27-treated mice, and Cx43-knockdown astrocytes. Astrocytic Cx43 overexpression and celecoxib treatment were tested as a potential therapeutic to rescue Cx43 function.

Results: Mice microinjected with RBD into the mPFC exhibited significant depressive-like behaviors, decreased neuronal excitability, and disrupted functional connectivity, accompanied by a marked reduction in astrocytic Cx43 expression and impaired GJIC. Functional assays, including Lucifer Yellow, cAMP, and cGAMP transfer, confirmed compromised gap junction activity, which was further associated with enhanced astrocytic type I interferon responses and cGAS-STING pathway activation. Conditional knockout of Cx43 in astrocytes or pharmacological inhibition of GJIC mimicked the depressive-like phenotypes induced by RBD. Importantly, Astrocytic Cx43 overexpression and celecoxib treatment restored GJIC, and effectively alleviated depressive-like behaviors in RBD-injected mice.

Conclusions: Astrocytic Cx43-mediated GJIC as a promising therapeutic strategy for managing depression in long COVID.

Keywords

Astrocyte; Cx43; Depression; Gap junction; Long COVID; SARS-CoV-2.

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