PNAS 1999-04-27

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

M E Bach, M Barad, H Son, M Zhuo, Y F Lu, R Shih, I Mansuy, R D Hawkins, E R Kandel

Index: Proc. Natl. Acad. Sci. U. S. A. 96(9) , 5280-5, (1999)

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Abstract

To study the physiological and molecular mechanisms of age-related memory loss, we assessed spatial memory in C57BL/B6 mice from different age cohorts and then measured in vitro the late phase of hippocampal long-term potentiation (L-LTP). Most young mice acquired the spatial task, whereas only a minority of aged mice did. Aged mice not only made significantly more errors but also exhibited greater individual differences. Slices from the hippocampus of aged mice exhibited significantly reduced L-LTP, and this was significantly and negatively correlated with errors in memory. Because L-LTP depends on cAMP activation, we examined whether drugs that enhanced cAMP would attenuate the L-LTP and memory defects. Both dopamine D1/D5 receptor agonists, which are positively coupled to adenylyl cyclase, and a cAMP phosphodiesterase inhibitor ameliorated the physiological as well as the memory defects, consistent with the idea that a cAMP-protein kinase A-dependent signaling pathway is defective in age-related spatial memory loss.