Desmosome is a cell structure for cell-to-cell adhesion in epithelia and cardiac muscles. Desmoplakin, a component of desmosome, is highly expressed in the dentate gyrus (DG) in the brain, although there is no evidence for desmosome structures in neurons. We previously found that the expression of desmoplakin in mouse hippocampus is decreased by antidepressant treatments, including selective serotonin reuptake inhibitors (SSRIs) and electroconvulsive stimulation (ECS), a model of electroconvulsive therapy. However, the role of desmoplakin in depressive-like behaviors has been unknown. In this study, we examined the contribution of knockdown of desmoplakin to depressive-like behaviors. To knockdown desmoplakin, we generated adeno associated virus expressing artificial microRNA targeting desmoplakin and injected it into the mouse DG. LPS was intraperitoneally administered, and sucrose preference and forced swim tests were used for assessing depressive-like behaviors. Knockdown of desmoplakin in the DG partly attenuated LPS-induced depressive-like behaviors. These results implicate that down-regulation of desmoplakin expression by antidepressant treatment may be involved in antidepressant effects in the hippocampus.