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      Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents

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          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 PI3K/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.

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          Most cited references 29

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          Synaptic plasticity, memory and the hippocampus: a neural network approach to causality.

          Two facts about the hippocampus have been common currency among neuroscientists for several decades. First, lesions of the hippocampus in humans prevent the acquisition of new episodic memories; second, activity-dependent synaptic plasticity is a prominent feature of hippocampal synapses. Given this background, the hypothesis that hippocampus-dependent memory is mediated, at least in part, by hippocampal synaptic plasticity has seemed as cogent in theory as it has been difficult to prove in practice. Here we argue that the recent development of transgenic molecular devices will encourage a shift from mechanistic investigations of synaptic plasticity in single neurons towards an analysis of how networks of neurons encode and represent memory, and we suggest ways in which this might be achieved. In the process, the hypothesis that synaptic plasticity is necessary and sufficient for information storage in the brain may finally be validated.
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            Long-term depression in the CNS.

            Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.
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              LTP inhibits LTD in the hippocampus via regulation of GSK3beta.

              Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                emmm
                EMBO Molecular Medicine
                BlackWell Publishing Ltd (Oxford, UK )
                1757-4676
                1757-4684
                July 2014
                30 May 2014
                : 6
                : 7
                : 902-917
                Affiliations
                [1 ]Centro Biología Molecular “Severo Ochoa” CSIC-UAM Madrid, Spain
                [2 ]VIB Center for the Biology of Disease, Center for Human Genetics, University of Leuven (KU Leuven) Leuven, Belgium
                [3 ]Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven (KU Leuven) Leuven, Belgium
                [4 ]Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal – CSIC Madrid, Spain
                [5 ]Departamento de Psicobiología, Facultad de Psicología, UNED Madrid, Spain
                [6 ]IFEG-CONICET and FaMAF, Universidad Nacional de Córdoba Córdoba, Argentina
                Author notes
                *Corresponding author. Tel: +54 351 4681465; E-mail: mauricio.m@ 123456immf.uncor.edu
                **Corresponding author. Tel: +34 911964401; E-mail: cdotti@ 123456cbm.csic.es

                Subject Categories Aging; Metabolism; Neuroscience

                Article
                10.15252/emmm.201303711
                4119354
                24878762
                © 2014 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Articles

                Molecular medicine

                pi3k, learning, cholesterol, aging, ltd

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