An enriched environment ameliorates memory impairments in PACAP-deficient mice

• Adult PACAP−/− mice displayed fear memory dysfunction and cognitive impairments.
• Rearing of PACAP−/− mice in an EE for 4 weeks ameliorated the memory impairments.
• The effects of EE on impaired memory were long-lasting.
• EE increased hippocampal NR2B subunit, phospho-ERK, phospho-CaMKII, and BDNF.
• The changes in the memory-related proteins may be involved in the effect of an EE.

We previously found that juvenile pituitary adenylate cyclase-activating polypeptide (PACAP)-knockout (PACAP−/−) mice reared in an enriched environment (EE) for 4 weeks showed attenuated hyperactivity, jumping behavior, impairments in social interaction, and depression-like behavior. The present study examined the effects of EE on memory function and memory-related protein levels in PACAP−/− mice. Eight-week-old PACAP−/− mice displayed fear memory dysfunction in a contextual fear conditioning test and cognitive impairments in a novel object recognition test. Rearing of 4-week-old PACAP−/− mice in an EE for 4 weeks ameliorated these memory impairments. The beneficial effects of EE were also observed 2 weeks after a return to housing in a standard environment (SE). This suggests that the effects of EE on impaired memory are long-lasting. In both wild-type and PACAP−/− mice, EE increased the protein levels of the NMDA receptor NR2B subunit, phospho-ERK, phospho-CaMKII, and brain-derived neurotrophic factor (BDNF) in the hippocampus, and decreased neurotrophin-3 levels, whereas it did not affect nerve growth factor and glial cell-derived neurotrophic factor levels. Increased levels of NR2B, phospho-ERK, phospho-CaMKII and BDNF were not observed 2 weeks after a return to housing in a SE. These findings suggest that living in an EE engenders long-lasting reductions in memory impairments in PACAP−/− mice. The present study also implies that increases in hippocampal memory-related protein and BDNF levels are responsible for the beneficial effects of an EE, but not for the maintenance of these effects.