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

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 β-arrestin (βArr)-dependent β-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of β-adrenergic receptors (β-ARs; members of the G protein-coupled receptor family), and βArrs as well as spatial learning and memory in aged male rats to determine whether β-AR/βArr 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 β1- and β2-ARs as well as βArr1 and βArr2 was performed. Spatial learning and memory were evaluated with the Morris water maze. The results showed significant up-regulation of β1-ARs as well as significant down-regulation of β2-AR and βArrs (βArr1 and βArr2) 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 β-ARs dysregulation and increase in βArr2 levels after exercise. There was a negative association between the expression of βArr2 and β1-AR, but not β2-AR, such that an increase in βArr2 by exercise was associated with reduced β1-AR expression, suggesting βArr2 may contribute to posttranslational down-regulation of β1-ARs. These data suggest that both G protein-dependent and β-arrestin-dependent β-AR pathways may regulate spatial learning and memory in aging brain.