Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents

Abstract

Cognitive decline is one of the many characteristics of aging.Reduced long-term potentiation (LTP) and long-term depression(LTD) are thought to be responsible for this decline, although theprecise mechanisms underlying LTP and LTD dampening in the oldremain unclear. We previously showed that aging is accompaniedby the loss of cholesterol from the hippocampus, which leads toPI3K/Akt phosphorylation. Given that Akt de-phosphorylation isrequired for glutamate receptor internalization and LTD, wehypothesized that the decrease in cholesterol in neuronalmembranes may contribute to the deficits in LTD typical of aging.Here, we show that cholesterol loss triggers p-Akt accumulation,which in turn perturbs the normal cellular and molecularresponses induced by LTD, such as impaired AMPA receptor inter-nalization and its reduced lateral diffusion. Electrophysiologyrecordings in brain slices of old mice and in anesthetized elderlyrats demonstrate that the reduced hippocampal LTD associatedwith age can be rescued by cholesterol perfusion. Accordingly,cholesterol replenishment in aging animals improves hippocampal-dependent learning and memory in the water maze test.