Age-related memory vulnerability to interfering stimuli is caused by gradual loss of MAPK-dependent protection in Drosophila.

Age-related memory impairment (AMI) is a common phenomenon across species. Vulnerability to interfering stimuli has been proposed to be an important cause of AMI. However, the molecular mechanisms underlying this vulnerability-related AMI remain unknown. Here we show that learning-activated MAPK signals are gradually lost with age, leading to vulnerability-related AMI in Drosophila. Young flies (2- or 3-day-old) exhibited a significant increase in phosphorylated MAPK levels within 15 min after learning, whereas aged flies (25-day-old) did not. Compared to 3-day-old flies, significant 1 h memory impairments were observed in 15-, 20-, and 30-day-old flies, but not in 10-day-old flies. However, with post-learning interfering stimuli such as cooling or electric stimuli, 10-day-old flies had worse memory performance at 1 h than 3-day-old flies, showing a premature AMI phenomenon. Increasing learning-activated MAPK signals through acute transgene expression in mushroom body (MB) neurons restored physiological trace of 1 h memory in a pair of MB output neurons in aged flies. Decreasing such signals in young flies mimicked the impairment of 1 h memory trace in aged flies. Restoring learning-activated MAPK signals in MB neurons in aged flies significantly suppressed AMI even with interfering stimuli. Thus, our data suggest that age-related loss of learning-activated neuronal MAPK signals causes memory vulnerability to interfering stimuli, thereby leading to AMI.