Continuous GSK-3β overexpression in the hippocampal dentate gyrus induces prodepressant-like effects and increases sensitivity to chronic mild stress in mice.

BACKGROUND

Glycogen synthase kinase-3 (GSK-3) has been linked to prodepressant-like effects in rodents. However, the roles of GSK-3β and the hippocampal dentate gyrus in regulating these behavioral effects remain unclear.

METHODS

A lentiviral vector was utilized to site-specifically express GSK-3β constitutively in the hippocampal DG in a mouse model of CMS. We examine the forced swim, tail suspension and the sucrose intake test. Acute and chronic administrations were conducted by dissolving fluoxetine hydrochloride (10ml/kg). We examine behavior tests as before, cellular apoptosis, proliferation and differentiation in the hippocampus.

RESULTS

GSK-3β expression levels persistently and significantly increased in the hippocampus following lenti-GSK-3β injections. In mice previously exposed to CMS, pre-injection of lentivirus-expressing GSK-3β into the hippocampal dentate gyrus significantly decreased sucrose preferences in the sucrose intake test and increased immobility times in both forced swim and tail suspension tests. In addition, fluoxetine resulted in similar antidepressant-like effects following chronic, but not acute, administrations under the same experimental conditions. Cellular apoptosis was observed in the hippocampal DG using TUNEL, revealing many TUNEL-positive cells in the lenti-GSK-3β mice. There were no significant changes in proliferation and differentiation.

LIMITATIONS: We did not measure more biomarkers which were regulated by GSK-3β.

CONCLUSIONS

Results from this study demonstrated that site-specific injection of a lentivirus induced continuous GSK-3β expression in the hippocampal dentate gyrus of mice, resulting in prodepressant-like effects and increased sensitivity to chronic mild stress. Furthermore, chronic fluoxetine administration reversed these prodepressant-like effects and decreased neuronal apoptosis in the hippocampal DG in GSK-3β-overexpressing mice.