Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuatedby drugs that enhance the cAMP signaling pathway

To study the physiological and molecular mechanisms of age-related memory l oss, we assessed spatial memory in C57BL/B6 mice from different age cohorts and then measured in vitro the late phase of hippocampal longterm potentia tion (L-LTP), Most young mice acquired the spatial task, whereas only a min ority of aged mice did, Aged mice not only made significantly more errors b ut also exhibited greater individual differences, Slices from the hippocamp us of aged mice exhibited significantly reduced L-LTP, and this was signifi cantly and negatively correlated with errors in memory. Because L-LTP depen ds on cAMP activation, we examined whether drugs that enhanced cAMP would a ttenuate the L-LTP and memory defects, Both dopamine D1/D5 receptor agonist s, which are positively coupled to adenylyl cyclase, and a cAMP phosphodies terase inhibitor ameliorated the physiological as well as the memory defect s, consistent with the idea that a cAMP-protein kinase A-dependent signalin g pathway is defective in age-related spatial memory loss.