Overexpression of type I adenylyl cyclase in the forebrain impairs spatial memory in aged but not young mice.

Hippocampus-dependent memory requires a cAMP signal that is generated by Ca2+-stimulated adenylyl cyclases (AC1, AC8). Young transgenic mice overexpressing AC1 in the forebrain (AC1+ mice) have enhanced hippocampal long-term potentiation, superior memory for novel object recognition and more persistent remote contextual memory. To determine whether increasing AC1 expression improves memory when older mice are trained, we analyzed fear, recognition, and spatial memory in mice aged to 25 months. Here we report that young adult AC1+ mice have enhanced social recognition memory, and normal fear and spatial memory. Surprisingly, aged AC1+ mice had poorer spatial memory than age-matched wild-type littermates. These data suggest that the decrease in Ca2+-stimulated adenylyl cyclase activity during aging of wild-type mice may be an adaptive mechanism required to maintain spatial memory function.