Mice lacking the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) (PACAP(-/-)) display behavioral abnormalities, and genetic variants of the genes encoding PACAP are associated with schizophrenia. Clinical studies show that environmental factors, besides genetic factors, play a key role in etiology of many psychiatric disorders. This study examined the effects of environmental factors such as short-term social isolation and an enriched environment on behavioral abnormalities of PACAP(-/-) mice. Rearing in isolation for 2-weeks from 4-weeks old induced hyperlocomotion and aggressive behaviors in the PACAP(-/-) mice without affecting the behavioral performance of the wild-type controls. Adult PACAP(-/-) mice showed not only hyperactivity, jumping behavior, and depression-like behavior, but also decreased social interaction. These abnormal behaviors were improved by rearing for 4-weeks in an early enriched environment (from 4-weeks old), although the deficits of prepulse inhibition (PPI) were not influenced by the enriched condition. In contrast, rearing for 4-weeks in late enriched environment (from 8-weeks old) did not affect the hyperactivity and jumping behaviors in the PACAP(-/-) mice. These results suggest that abnormal behaviors except PPI deficits in PACAP(-/-) mice depend on the environmental factors during the early stages of development.
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