Wnt5a-AS knockdown alleviates sevoflurane-induced depression by promoting hippocampal neurogenesis and mitochondrial fusion in adolescent rats.

BACKGROUND

Early-life exposure to sevoflurane induces depressive-like behaviors and cognitive deficits in adolescent rodents (ELSDs) in adolescent rodents. Although hippocampal neurogenesis in the subgranular zone (SGZ) has been implicated in mental disorders, the role of Wnt5a-AS in onset of ELSDs remains unclear. We investigated whether Wnt5a-AS knockdown restores neurogenesis and mitochondrial dynamics to ameliorate ELSDs.

METHODS

After exposure to sevoflurane or control gas early in life, adolescent rats were subjected to open field test, sucrose preference test, forced swim test, and Morris water maze test. Wnt5a-AS was knocked down with rAAV. Hippocampal neurogenesis was assessed by immunofluorescence. The levels of mitochondrial dynamics-associated proteins were assessed by western blotting. Mitochondrial reactive oxygen species (mtROS) levels were measured by flow cytometry, and mitochondria were labeled with Tom20.

RESULTS

Rats that were exposed to sevoflurane in life exhibited depressive-like behaviors and a decline in cognition. Sevoflurane increased Wnt5a-AS expression, inhibited neurogenesis, and elevated mtROS production in the SGZ. In addition, sevoflurane increased the expression of Mitofusin1/2, Optic Atrophy 1, Drp1p-Ser637 and Drp1Ser616 but not Dynamin-related protein-1(Drp1). In the SGZ, Wnt5a-AS knockdown ameliorated ELSDs, promoted neurogenesis and mitochondrial fusion, decreased mtROS levels, and increased Drp1p-Ser637 and Drp1Ser616 levels.

CONCLUSION

Collectively, these findings indicate that Wnt5a-AS knockdown alleviates ELSDs by restoring neurogenesis in the hippocampal SGZ by increasing mitochondrial fusion. These findings establish Wnt5a-AS as a potential therapeutic target for mitigating ELSDs-associated neurodevelopmental deficits in rodents, warranting further validation in higher species.