OGT-related mitochondrial motility is associated with sex differences and exercise effects in depression induced by prenatal exposure to glucocorticoids

Background: Prenatal exposure to glucocorticoids (GCs) has been found to trigger abnormal behaviors and deleterious neurological effects on offspring both in animals and in humans. The sex differences in depression have been replicated in numerous studies across cultures, persisting throughout the reproductive years. As an X-linked gene in rodents and in humans, O-GlcNAc transferase (OGT) may provide a novel perspective for the sex differences in depression. Methods: In the last third of pregnancy (gestational day 14-21), rats were subcutaneously administered either 0.13 mg/kg dexamethasone-21-phosphate disodium salt (0.1 mg/kg DEX) or vehicle (0.9% saline) once a day for 7 days. Adolescent (4 weeks) offspring were then trained in a swimming program or not. Results: Here we found that adult offspring rats exposed to DEX prenatally exhibited sex-specific depression-like behaviors, males being more vulnerable than females. Swimming exercise ameliorated the above-mentioned depressive syndromes, which may be a compensatory effect for male disadvantage suffering from prenatal stress. Furthermore, the effects of prenatal DEX exposure and swimming exercise on depression were associated with OGT-related mitochondrial motility, including PINK1/Parkin pathway and AKT/GSK3 beta pathway. Limitations: Representative kymographs of mitochondrial motility were not detected and no causal effects were obtained by OGT gene overexpression or gene knockout in this study. Conclusions: Our results provide a new perspective for better understanding sex differences and exercise effects in depression and may offer new mechanism-based therapeutic targets for depression.