GPR55 deletion increases anxiety- and depression-like behaviors and modifies amygdalar GABAAα2 expression

Abstract

Introduction 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. Methods 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 GABAA 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. Results GPR55 deletion increased anxiety- and depressive-like behaviors across all the behavioral paradigms evaluated. GABAAα2 gene expression in the AMY was elevated in GPR55KO mice of both sexes, while GABAAγ2 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. Discussion 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.