Disrupted‐in‐schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1Δ2‐3/Δ2‐3 mice), which have a deficiency of the full‐length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen‐based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1Δ2‐3/Δ2‐3 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild‐type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1Δ2‐3/Δ2‐3 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1Δ2‐3/Δ2‐3 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c‐Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1Δ2‐3/Δ2‐3 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine‐N‐oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1Δ2‐3/Δ2‐3 mice are associated with hyperactivity of the DMS.
