<b><i>Background:</i></b> The incidence of depression is twice higher in women than in men, and gender differences in the prevalence rates first emerge around puberty. Prenatal stress (PS) induces gender-dependent depressive-like behavior in adolescent offspring, but the neuro-physiological mechanisms remain unclear. Our study aimed to investigate the possible neuro-physiological mechanisms of gender-dependent depressive-like behavior in PS adolescent offspring and further explored the possibility of treating depression in adolescent female rats. <b><i>Methods:</i></b> The pregnant rats were exposed to restraint stress in the third trimester for 7 days. The depressive-like behavior and the expression of N-cadherin and AMPARs in the hippocampus of adolescent offspring rats were assessed. 10 mg/kg AMPAR antagonist CNQX and 10 mg/kg N-cadherin antagonist ADH-1 were intraperitoneally injected into female adolescent offspring, respectively; 0.2 µg AMPAR agonist CX546 was administered to the dentate gyrus of male adolescent offspring to determine the role of N-cadherin-AMPARs in depressive-like behavior of the offspring following PS. <b><i>Results:</i></b> We found that PS increased N-cadherin expression, which upregulated GluA1 expression in the dentate gyrus, mediating depressive-like behavior in adolescent female rat offspring by reducing PSD-95. In addition, ADH-1 and CNQX improved depressive-like behavior in adolescent female offspring following PS. Furthermore, injection of the CX546 into the dentate gyrus induced depressive-like behavior in PS male offspring. <b><i>Conclusion:</i></b> The gender-dependent expression of N-cadherin-GluA1 pathway in adolescent offspring in the dentate gyrus was the key factor in gender differences of depressive-like behavior following PS.

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