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

TLDR

The study investigates age‑related spatial memory loss by testing spatial task performance in C57BL/6 mice of different ages and measuring hippocampal late‑phase long‑term potentiation, and examines whether enhancing cAMP signaling can mitigate these deficits. Researchers assessed spatial memory in young and aged mice, recorded in vitro late‑phase L‑LTP from hippocampal slices, and administered dopamine D1/D5 agonists and a cAMP phosphodiesterase inhibitor to evaluate their effects on L‑LTP and memory. Aged mice performed poorly on the spatial task, made more errors, and showed greater variability; their hippocampal slices exhibited reduced L‑LTP that negatively correlated with memory errors, and both cAMP‑enhancing drugs improved L‑LTP and memory performance, indicating a defective cAMP‑PKA pathway in aging.

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.