GPR55 deletion increases anxiety- and depression-like behaviors and modifies amygdalar GABA_Aα2 expression

GPR55 has attracted attention for its anti-inflammatory, neuroprotective, and neurotransmitter-modulating properties, suggesting a role in mood regulation. Here, we aimed to clarify the contribution of GPR55 to emotional responses.

Male and female GPR55 knockout (GPR55KO) and wild-type (WT) C57BL/6J mice were evaluated in the light-dark box, elevated plus maze, social interaction and tail suspension tests. Gene expression of the GABA_A receptor α2 and γ2 subunits was measured in the amygdala (AMY). A separate cohort underwent 30 min of restraint stress to assess hypothalamic-pituitary-adrenal (HPA) axis markers, including the expression of the Crf and Nrc3c1 genes in the paraventricular nucleus (PVN) and in the hippocampus.

GPR55 deletion increased anxiety- and depressive-like behaviors across all the behavioral paradigms evaluated. GABA_Aα₂ gene expression in the AMY was elevated in GPR55KO mice of both sexes, while GABA_Aγ₂ expression was not influenced by genotype. Restraint stress increased Crf and reduced Nr3c1 similarly across genotypes. Notably, male GPR55KO mice displayed lower basal Crf levels than male controls.

Together, these findings indicate that loss of GPR55 heightens emotional vulnerability and alters specific GABAergic markers in the AMY while preserving HPA axis-related transcriptional response to acute stress. These results support GPR55 as a potential target for the modulation of anxiety- and depression-related states.