Depression-resistant Phenotype in Mice Overexpressing Regulator of G Protein Signaling 8 (RGS8)

•RGS8 transgenic mice (RGS8tg) overexpressing RGS8 protein in the hippocampal CA1 exhibit antidepressant-like behavior.•Desipramine treatment further reduced the immobility time in RGS8tg in the forced swimming test.•Administration of MCHR1 antagonist SNAP94847 to RGS8tg had no effect on the immobility time in the forced swimming test.•MCHR1-positive primary cilia are significantly elongated in the CA1 of RGS8tg, compared with that in wild mice.•Depression-like behavior in RGS8tg might result through RGS8-ciliary MCHR1 interaction in the CA1 region. Regulator of G protein signaling (RGS) proteins are negative regulators of heterotrimeric G proteins that act by accelerating Gα-mediated GTPase activity to terminate G protein-coupled receptor-associated signaling. RGS8 is expressed in several brain regions involved with movement and mood. To investigate the role of RGS8 in vivo, we generated transgenic mice overexpressing brain RGS8 (RGS8tg). RGS8 gene and protein expressions were examined by real-time PCR and immunohistochemistry, respectively, and a significant increase in RGS8 protein was detected in the hippocampal CA1 region compared with wild-type mice (WT). We characterized the phenotypic traits, and found that RGS8tg showed decreased depressive-like behavior in the forced swimming test (FST). Previously, RGS8 was identified as a potent negative regulator of melanin-concentrating hormone receptor 1 (MCHR1), whose activation is mainly involved in energy homeostasis and emotional processing. Interestingly, acute oral administration of MCHR1 antagonist SNAP94847 did not have antidepressant-like effects on RGS8tg in the FST, but did show antidepressant effects on WT. In contrast, selective noradrenaline reuptake inhibitor desipramine had a significant effect on RGS8tg in the FST. MCHR1 is enriched in a subset of primary cilia, as sensory organelles that mediate extracellular signaling. Immunohistochemical analyses revealed significant elongation of MCHR1-positive cilia in the CA1 region of RGS8tg compared with WT. Taken together, these findings suggest that RGS8 participates in modulation of depression-like behavior through ciliary MCHR1 expressed in the CA1 region. The present study may support the possible modulation of RGS8 function in mood disorders.