Alteration of CREB phosphorylation and spatial memory deficits in aged 129T2/Sv mice.

Phosphorylation of cAMP-response element binding protein (CREB) is required for hippocampus-dependent long-term memory formation. The present study was designed to determine whether spatial memory deficits in aged mice were associated with alteration of hippocampal CREB phosphorylation. We examined the temporal pattern of CREB activation in 5-6 and 23-24-month-old 129T2/Sv mice trained on a spatial reference memory task in the water maze. Phosphorylated CREB (pCREB), total CREB (t-CREB) and c-Fos immunoreactivity (ir) were measured at four time points after the end of training. In young mice, pCREB-ir was significantly increased 15 and 60 min after training in the CA1 region and dentate gyrus. In aged mice sacrificed 15 min after training, pCREB-ir in these structures was reduced whereas t-CREB-ir remained unchanged compared to respective young-adults. An age-related reduction of c-Fos-ir also occurred selectively in hippocampal CA1 region. Since reduced pCREB-ir in CA1 from the 15 min-aged group strongly correlated with individual learning performance, we suggest that altered CREB phosphorylation in CA1 may account for spatial memory impairments during normal aging.