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 the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, which leads to PI 3K/Akt phosphorylation. Given that Akt de‐phosphorylation is required for glutamate receptor internalization and LTD , we hypothesized that the decrease in cholesterol in neuronal membranes 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 molecular responses induced by LTD , such as impaired AMPA receptor internalization and its reduced lateral diffusion. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Accordingly, cholesterol replenishment in aging animals improves hippocampal‐dependent learning and memory in the water maze test. image It is well established that cognitive deficits go hand in hand with aging. Restoring cholesterol levels in the aged hippocampus to values found in the young can rescue learning and memory in the old, linking age‐dependent cholesterol decline with synaptic plasticity and neuronal function. A mild yet significant reduction in membrane cholesterol characterizes the aging rodent hippocampus. Low synaptic hippocampal cholesterol determines reduced Akt dephosphorylation after NMDA ‐induced LTD , together with reduced glutamate ( AMPA ) receptor lateral diffusion and endocytosis. Low synaptic hippocampal cholesterol plays a role in the poor LTD of old mice and rats, in ex‐vivo and in vivo paradigms. Normal levels of pA kt after NMDA, proper receptor lateral diffusion, and internalization and normal (young animals‐like) LTD in the old can be rescued by membrane cholesterol replenishment. Cholesterol replenishment in living old rats improves learning and memory.