The neuroprotective effects of GPR55 against hippocampal neuroinflammation and impaired adult neurogenesis in CSDS mice

Neurobiol Dis. 2022 Jul:169:105743. doi: 10.1016/j.nbd.2022.105743. Epub 2022 Apr 28.


Depression is one of the most prevalent mental illnesses in the world today, and the onset of depression is usually accompanied by neuroinflammation and impaired adult neurogenesis. As a new potential member of the endocannabinoid (eCB) system, G protein coupled receptor 55 (GPR55) has been associated with mood regulation. However, the role of GPR55 in the pathophysiology of depression remains poorly understood. Thus, a 10-day chronic social defeat stress (CSDS) paradigm was utilized as an animal model of depression to explore the potential role of GPR55 in depression. After CSDS, the protein level of GPR55 decreased significantly, but the mRNA expression did not change significantly, highlighting that although the GPR55 protein was involved in the progression of the depression- and anxiety-like phenotypes, its mRNA was not. Additionally, depression- and anxiety-like behaviors were also accompanied by neuroinflammation and impaired adult neurogenesis in the hippocampus. Interestingly, O-1602, a GPR55 agonist, remarkably prevented the development of depression- and anxiety-like behaviors as well as hippocampal neuroinflammation and neurogenesis deficits induced by CSDS. However, after electroacupuncture (EA) alleviated depression- and anxiety-like behaviors induced by CSDS, treatment with a GPR55 antagonist (CID16020046) reversed this effect. Our research demonstrated that downregulation of GPR55 expression in the hippocampus might mediate CSDS-induced depression- and anxiety-like phenotypes, and activation and upregulation of GPR55, which might be correlated with its anti-inflammatory and subsequent neuroprotective effects, could be a potential treatment for depression.

Keywords: Chronic social defeat stress; Depression; GPR55; Neurogenesis; Neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Depression / metabolism
  • Hippocampus / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neurogenesis / physiology
  • Neuroinflammatory Diseases
  • Neuroprotective Agents* / pharmacology
  • Receptors, Cannabinoid / metabolism
  • Social Defeat*
  • Stress, Psychological / complications


  • GPR55 protein, mouse
  • Neuroprotective Agents
  • Receptors, Cannabinoid