Constitutive Hippocampal Cholesterol Loss Underlies Poor Cognition in Old Rodents

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2014 Jun 1

PMID 24878762

Citations 44

Authors

Mauricio G Martin

Tariq Ahmed

Alejandra Korovaichuk

Cesar Venero

Silvia A Menchon

Isabel Salas

Sebastian Munck

Oscar Herreras

Detlef Balschun

Carlos G Dotti

Affiliations

Soon will be listed here.

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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References

Trovo L, Ahmed T, Callaerts-Vegh Z, Buzzi A, Bagni C, Chuah M . Low hippocampal PI(4,5)P₂ contributes to reduced cognition in old mice as a result of loss of MARCKS. Nat Neurosci. 2013; 16(4):449-55. DOI: 10.1038/nn.3342. View

Martin M, Trovo L, Perga S, Sadowska A, Rasola A, Chiara F . Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons. Neurobiol Aging. 2009; 32(5):933-43. DOI: 10.1016/j.neurobiolaging.2009.04.022. View

Arbuzova A, Murray D, McLaughlin S . MARCKS, membranes, and calmodulin: kinetics of their interaction. Biochim Biophys Acta. 1998; 1376(3):369-79. DOI: 10.1016/s0304-4157(98)00011-2. View

Morris R . Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11(1):47-60. DOI: 10.1016/0165-0270(84)90007-4. View

Arendt K, Royo M, Fernandez-Monreal M, Knafo S, Petrok C, Martens J . PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane. Nat Neurosci. 2009; 13(1):36-44. PMC: 2810846. DOI: 10.1038/nn.2462. View

Groc L, Heine M, Cognet L, Brickley K, Stephenson F, Lounis B . Differential activity-dependent regulation of the lateral mobilities of AMPA and NMDA receptors. Nat Neurosci. 2004; 7(7):695-6. DOI: 10.1038/nn1270. View

Lund E, Xie C, Kotti T, Turley S, Dietschy J, Russell D . Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem. 2003; 278(25):22980-8. DOI: 10.1074/jbc.M303415200. View

Ledesma M, Martin M, Dotti C . Lipid changes in the aged brain: effect on synaptic function and neuronal survival. Prog Lipid Res. 2011; 51(1):23-35. DOI: 10.1016/j.plipres.2011.11.004. View

Jurado S, Benoist M, Lario A, Knafo S, Petrok C, Esteban J . PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J. 2010; 29(16):2827-40. PMC: 2924645. DOI: 10.1038/emboj.2010.160. View

10.

Paxinos G, Watson C, Pennisi M, Topple A . Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods. 1985; 13(2):139-43. DOI: 10.1016/0165-0270(85)90026-3. View

11.

Carroll R, Lissin D, von Zastrow M, Nicoll R, Malenka R . Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nat Neurosci. 1999; 2(5):454-60. DOI: 10.1038/8123. View

12.

Diamond D, Park C, Campbell A, Woodson J . Competitive interactions between endogenous LTD and LTP in the hippocampus underlie the storage of emotional memories and stress-induced amnesia. Hippocampus. 2005; 15(8):1006-25. DOI: 10.1002/hipo.20107. View

13.

Martin M, Perga S, Trovo L, Rasola A, Holm P, Rantamaki T . Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro. Mol Biol Cell. 2008; 19(5):2101-12. PMC: 2366859. DOI: 10.1091/mbc.e07-09-0897. View

14.

Ahmed T, Sabanov V, DHooge R, Balschun D . An N-methyl-D-aspartate-receptor dependent, late-phase long-term depression in middle-aged mice identifies no GluN2-subunit bias. Neuroscience. 2011; 185:27-38. DOI: 10.1016/j.neuroscience.2011.04.006. View

15.

Burke S, Barnes C . Neural plasticity in the ageing brain. Nat Rev Neurosci. 2005; 7(1):30-40. DOI: 10.1038/nrn1809. View

16.

Zheng W, Quirion R . Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J Neurochem. 2004; 89(4):844-52. DOI: 10.1111/j.1471-4159.2004.02350.x. View

17.

Man H, Wang Q, Lu W, Ju W, Ahmadian G, Liu L . Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron. 2003; 38(4):611-24. DOI: 10.1016/s0896-6273(03)00228-9. View

18.

Nicholls R, Alarcon J, Malleret G, Carroll R, Grody M, Vronskaya S . Transgenic mice lacking NMDAR-dependent LTD exhibit deficits in behavioral flexibility. Neuron. 2008; 58(1):104-17. DOI: 10.1016/j.neuron.2008.01.039. View

19.

Wenthold R, Petralia R, Blahos J I, Niedzielski A . Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J Neurosci. 1996; 16(6):1982-9. PMC: 6578515. View

20.

Ge Y, Dong Z, Bagot R, Howland J, Phillips A, Wong T . Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci U S A. 2010; 107(38):16697-702. PMC: 2944752. DOI: 10.1073/pnas.1008200107. View