Exercise may alleviate age-related spatial memory impairment by rescuing 0-adrenergic receptor dysregulation via both G protein-dependent and 0-arrestin-dependent mechanisms in rat hippocampus

Abstract

Hippocampal-dependent memory abilities including spatial memory decline with age. Exercise improves memory decline in aging brain, but, the precise mechanisms are still unknown. Learning and memory are recently hypothesized to be mediated by a 0-arrestin (0Arr)-dependent 0-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of 0-adrenergic receptors (0-ARs; members of the G protein-coupled receptor family), and 0Arrs as well as spatial learning and memory in aged male rats to determine whether 0-AR/0Arr pathway could be involved in age-related memory decline. A total of 24 young (3-month-old) and aged (18-month-old) male Wistar rats were divided into young control, aged sedentary, and aged + exercise (n = 8 for each). Western blot for 01- and 02-ARs as well as 0Arr1 and 0Arr2 was performed. Spatial learning and memory were evaluated with the Morris water maze. The results showed significant up-regulation of 01-ARs as well as significant down-regulation of 02-AR and 0Arrs (0Arr1 and 0Arr2) in the hippocampus of aged rats. Spatial memory, but not spatial learning, was impaired in aging, and treadmill exercise improved it. Notably, the improvement in spatial memory was accompanied by amelioration of 0-ARs dysregulation and increase in 0Arr2 levels after exercise. There was a negative association between the expression of 0Arr2 and 01-AR, but not 02-AR, such that an increase in 0Arr2 by exercise was associated with reduced 01-AR expression, suggesting 0Arr2 may contribute to posttranslational down-regulation of 01-ARs. These data suggest that both G protein-dependent and 0-arrestin-dependent 0-AR pathways may regulate spatial learning and memory in aging brain.