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Background: Deficiency of olfaction is thought to be associated with depression, and type 3 adenylyl cyclase (AC3) genetic knockout and forebrain knockout mice show depression-like behaviours. AC3 is expressed in the main olfactory epithelium (MOE) and hippocampus, which plays an important role in olfactory signal transduction. However, it is unclear whether AC3 in the MOE also plays a role in the pathogenesis of depression. Thus, we aimed to study the relationship between AC3 in the MOE and the pathogenesis of depression.Methods: We obtained anosmic mice by intranasal perfusion of zinc sulphate (ZnSO4) (ZnSO4 mice), and distinctively knocked down AC3 in the MOE (AC3KD/MOE mice) by CRISPR/cas9 technology. Behavioural tests related to depression and anxiety were employed to evaluate the depression- and anxiety-like behaviours of mice. The mRNA and protein expressions of tyrosine hydroxylase (TH), dopamine receptors (Drds), and N-Methyl D-aspartate receptor subunit 2B (GluN2B) in the hippocampus of mice were investigated by qPCR and western blotting to explore the mechanism of depression and anxiety caused by AC3 in the MOE, preliminarily.Results: Compared with NaCl mice, ZnSO4 mice exhibited depression-like behaviours in tail suspension tests (TST), forced swimming tests, and social (FST) interaction tests (SIT), but showed no anxiety-like behaviours in anxiety-related behavioural tests. The mRNA and protein expressions of Drd3 and GluN2B in the hippocampus of ZnSO4 mice were significantly downregulated. Compared with the negative control mice (NC mice), AC3KD / MOE mice showed depression-like behaviours in TST, FST, and SIT tests, anxiety-like behaviours in light/dark transition test, elevated-plus maze test, and novelty-suppressed feeding test. The protein expressions of Drd3, TH, and GluN2B were significantly downregulated in the hippocampus.Limitations: We did not further demonstrate that AC3 in the MOE causes depression through the dopaminergic nervous system with dopamine or dopamine receptor agonists.Conclusions: Our data demonstrate that intranasal infusion of ZnSO4 can cause depression-like behaviours and has no effect on anxiety-like behaviours. Specific knockdown of AC3 in the MOE can cause depression-like and anxiety-like behaviours. The behavioural changes caused by intranasal ZnSO4 and specific knockdown of AC3 in the MOE can be related to the significant downregulation of dopaminergic system and GluN2B expressions in the hippocampus of mice. [ABSTRACT FROM AUTHOR]