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mTORC2 controls actin polymerization required for consolidation of long-term memory

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Abstract

A major goal of biomedical research is the identification of molecular and cellular mechanisms that underlie memory storage. Here we report a previously unknown signaling pathway that is necessary for the conversion from short- to long-term memory. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which contains the regulatory protein Rictor (rapamycin-insensitive companion of mTOR), was discovered only recently and little is known about its function. We found that conditional deletion of Rictor in the postnatal murine forebrain greatly reduced mTORC2 activity and selectively impaired both long-term memory (LTM) and the late phase of hippocampal long-term potentiation (L-LTP). We also found a comparable impairment of LTM in dTORC2-deficient flies, highlighting the evolutionary conservation of this pathway. Actin polymerization was reduced in the hippocampus of mTORC2-deficient mice and its restoration rescued both L-LTP and LTM. Moreover, a compound that promoted mTORC2 activity converted early LTP into late LTP and enhanced LTM. Thus, mTORC2 could be a therapeutic target for the treatment of cognitive dysfunction.

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Figure 1: L-LTP, but not E-LTP, is impaired in mTORC2-deficient slices.
Figure 2: Long-term, but not short-term, fear memory is impaired in mTORC2-deficient mice.
Figure 3: In TORC2-deficient Drosophila, long-term spaced memory (but not massed) is impaired.
Figure 4: Actin dynamics, Rac1-GTPase activity and signaling are impaired in CA1 of Rictor fb-KO mice.
Figure 5: Restoring actin polymerization rescues the impaired L-LTP and contextual LTM caused by mTORC2 deficiency.
Figure 6: A-443654 promotes mTORC2 activity, actin polymerization and facilitates L-LTP in wild-type mice, but not in mTORC2-deficient mice.
Figure 7: A-443654 selectively enhances LTM in wild-type mice, but not in mTORC2-deficient mice.

Change history

  • 10 March 2013

    In the version of this article initially published online, acknowledgment of grant BCM IDDRC 5P30HD024064-23 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development to M.C.-M. was missing. The error has been corrected for the print, PDF and HTML versions of this article.

  • 10 March 2013

    In the version of this supplementary file originally posted online, in Supplementary Figure 11, the wrong images were provided for total S6K for Fig. 1a, β-actin for Figures 2a and 3a, actin (bottom) for Fig. 5a and p-Akt for Figure 6a, and the panels corresponding to Figures 6a, 6b, 6d and 6e were mislabeled 5b, 5c, 5d and 5e, respectively. The errors have been corrected in this file as of 10 March 2013.

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Acknowledgements

We thank M. Magnuson (Vanderbilt University), I. Dragatsis (University of Tennessee) and K. Tolias (Baylor College of Medicine) who generously provided RictorloxP/loxP mice, Camk2a-Cre mice and the Tiam1 constructs, respectively. We also thank A. Placzek and W. Sossin for comments on an early version of the manuscript. This work was supported by grants to M.C.-M. (National Institute of Mental Health grant MH 096816, National Institute of Neurological Disorders and Stroke grant NS 076708, Searle award grant 09-SSP-211, Whitehall award, grants from the George and Cynthia Mitchell Foundation, and Eunice Kennedy Shriver National Institute of Child Health & Human Development BCM IDDRC 5P30HD024064-23) and G.R. (US National Institutes of Health grant MH091305 and a Texas Norman Hackerman Advanced Research Program award).

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W.H., P.J.Z. and M.C.-M. conceived and designed the experiments. W.H. performed the behavioral, molecular and spine density experiments. P.J.Z. performed the electrophysiology experiments. H.Z. performed the Nissl staining experiments. G.R. and S.Z. performed and analyzed the Drosophila behavioral experiments. All of the authors discussed the results and commented on the manuscript. M.C.-M. wrote the manuscript with input from W.H., G.R., P.J.Z. and K.K.

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Correspondence to Mauro Costa-Mattioli.

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Huang, W., Zhu, P., Zhang, S. et al. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16, 441–448 (2013). https://doi.org/10.1038/nn.3351

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