Molecular mechanisms underlying age-dependent memory decline in Caenorhabditis elegans

Cognitive decline, particularly the decrease of memory, is a natural process during ageing. In a society with a growing elderly population, it is therefore critical to understand the impacts of aging on memory. This understanding may pave the way for finding new therapies to counteract physiological or pathological cognitive decline. From the many memory-related molecules, AMPA-type glutamate receptors are well known regulators of learning and memory, however their age-dependent alteration of dynamics, and their effect on age-dependent memory decline are largely unknown. Here, we investigated changes in the in vivo properties of the AMPA type glutamate receptor, GLR-1, during physiological ageing in the AVA interneuron of the C. elegans nervous system. We demonstrated that the abundance of total GLR-1 and membrane inserted GLR-1 receptors decreased with age in wild-type worms irrespective of the axonal position. Additionally, through the use of FRAP, we demonstrated that the reduction of GLR-1 abundance is associated with a decrease in the local synaptic receptor dynamics. Finally, the reduced GLR-1 levels strongly correlated with the observed age-dependent associative memory decline. In accordance, when we genetically manipulated GLR-1 stability through deletion of msi-1 or expression of the ubiquitination-defective GLR-1 (4KR), we did not observe the reduction of receptor abundance with age. Moreover, these alterations were able to restore memory in aged animals to the levels seen in young animals. Altogether, our results demonstrate that AMPA-type glutamate receptor abundance and turnover dynamics play a key role in sustaining memory performance, and that decreased GLR-1 abundance and alteration of receptor dynamics are associated with age-dependent memory decline.