Behavioural changes in young ovariectomized mice via GPR30-dependent serotonergic nervous system

Fluctuations in estradiol levels at each stage of life in women are considered one of the causes of mental diseases through their effects on the central nervous system. During menopause, a decrease in estradiol levels has been reported to affect the serotonin nervous system and induce depression-like and anxiety symptoms. However, the regulation of brain and behaviour during childhood and adolescence is poorly understood. Moreover, the role of oestrogen receptors α and β in the regulation of the serotonergic nervous system has been reported, but little is known about the involvement of G protein-coupled receptor 30. Therefore, in this study, we used an ovariectomized childhood mouse model to analyse behaviour and investigate the effects on the serotonin nervous system. We showed that ovariectomy surgery at 4 weeks of age, which is the weaning period, induced a decrease in spontaneous locomotor activity during the active period and a preference for novel mice over familiar mice in the three-chamber social test at 10 weeks of age. In addition, the administration of G-1, a protein-coupled receptor 30 agonist, to ovariectomized mice suppressed spontaneous locomotor activity and the preference for novel mice. Furthermore, we demonstrated that childhood ovariectomy induces increased tryptophan hydroxylase gene expression in the raphe nucleus and increased serotonin release in the amygdaloid nucleus, and administration of G-1 ameliorated these effects. Our study suggests that G protein-coupled receptor 30-mediated regulation of serotonin synthesis is involved in changes in activity and social-cognitive behaviour due to decreased estradiol levels during childhood.