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Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice as a result of loss of MARCKS

Abstract

Cognitive and motor performances decline during aging. Although it is clear that such signs reflect synaptic compromise, the underlying mechanisms have not been defined. We found that the levels and activity of the synaptic plasticity modulators phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2) and phospholipase Cγ (PLCγ) were substantially reduced in hippocampal synaptic membranes from old mice. In addition, these membranes contained reduced levels of the PI(4,5)P2-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS). Consistent with a cause-effect relationship, raising MARCKS levels in the brain of old mice led to increased synaptic membrane clustering of PI(4,5)P2 and to PLCγ activation. MARCKS overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide resulted in enhanced long-term potentiation and improved memory. These results reveal one of the mechanisms involved in brain dysfunction during aging.

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Figure 1: Age-associated changes in the levels of PI(4,5)P2, PI(3,4,5)P3, Akt and PLCγ in hippocampal synapses.
Figure 2: Low PI(4,5)P2 in aged mice leads to reduced PLCγ activity.
Figure 3: MARCKS expression in hippocampal neurons in vitro increases PI(4,5)P2 membrane levels.
Figure 4: Raising MARCKS levels in the hippocampi of old mice increases PLCγ activity.
Figure 5: MARCKS treatment corrects for age-associated deficits in activity dependent long-term synaptic plasticity.
Figure 6: Pharmacological attenuation of PI(4,5)P2 levels in young mice reproduces the LTP deficit observed in old mice.
Figure 7: Increasing MARCKS expression in the hippocampi of old mice improves memory retention, and has no effect on young mice.

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Acknowledgements

We thank K. Vennekens for technical assistance and P.J. Blackshear (National Institute of Environmental Health) for the MARCKS plasmids. This research was supported by the Fund for Scientific Research Flanders (FWO), the Federal Office for Scientific Affairs (IUAP P6/43), the Flemish Government's Methusalem Grant, a NEUROBRAINNET grant from the Belgian Government (IAP 7/16), and grants from the Spanish Ministry of Science and Innovation Ingenio-Consolider (CSD2010-00064 and SAF2010-14906) to C.G.D. L.T. is the recipient of a BOF-Post Doctoral Fellowship from the Research Fund of Katholieke University of Leuven. D.B. and R.D. are supported by a K.U. Leuven GOA (12/008) grant.

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L.T. participated in the design of all of the experiments and performed the in vivo and in vitro biochemical and microscopy experiments, the stereotactic injections, analyzed the data, and wrote the paper. T.A. and D.B. performed and analyzed the electrophysiological recordings. T.A. and D.B. wrote the relevant section of the manuscript. A.B. supervised the stereotactic injections. Z.C.-V. performed the behavioral tests and, together with R.D., helped with the writing of the relevant section of the manuscript. M.C. and T.V. produced the wild-type MARCKS and MARCKS-D/S mutant viruses. C.B. contributed to the supervision of the synaptosomal preparations. C.G.D. supervised the project, discussed the results and implications at all stages, and wrote the manuscript.

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Correspondence to Carlos G Dotti.

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Trovò, L., Ahmed, T., Callaerts-Vegh, Z. et al. Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice as a result of loss of MARCKS. Nat Neurosci 16, 449–455 (2013). https://doi.org/10.1038/nn.3342

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