Although high fat diet (HFD) is well known to induce obesity, detailed knowledge of its effect on mental illness has not yet been fully elucidated. We found that the HFD induced the disruption of prepulse inhibition (PPI) of acoustic startle response, a measurement of sensorimotor gating that is deficient in schizophrenia, after 10 weeks of HFD fed in 5 week-old male mice. The spontaneous locomotor activity was unchanged by the HFD compared to normal diet (ND) in the open-field test. The disruption of PPI was sustained even 4-week after the HFD finished. Western blot analysis revealed that glycogen synthase kinase (GSK)3α/β phosphorylation was increased while the amount of GSK3α/β protein did not change in the striatum of HFD mice. In addition, GSK3α/β protein expression was decreased in the prefrontal cortex of HFD mice. HFD also induced PPI disruption for dopamine D2 receptor KO mice. Although it was not significant, the D2 receptor KO mice showed lower PPI compared with the WT littermates. This is the first evidence that HFD significantly affects both phosphorylation and protein expression of GSK3α/β in the striatum and prefrontal cortex, respectively. These findings are consistent, at least in part, with previous postmortem studies in schizophrenia, suggesting that HFD mice may be a good animal model for schizophrenia.