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A critical role for IGF-II in memory consolidation and enhancement

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Abstract

We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

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Figure 1: C/EBPβ-dependent IGF-II expression significantly increases following training.
Figure 2: Hippocampal IGF-II is required for memory consolidation.
Figure 3: Hippocampal post-training IGF-II administration enhances memory and prevents forgetting.
Figure 4: Post-retrieval IGF-II administration enhances memory and the effect is temporally limited.
Figure 5: The role of IGF-II receptors, de novo protein synthesis and Arc in memory consolidation and IGF-II-mediated enhancement.
Figure 6: Mechanisms of IGF-II-mediated memory enhancement. IGF-II promotes LTP.

Change history

  • 17 October 2011

    In Supplementary Fig. 2 of this Article, the same western blot representative was inadvertently used for rows 1 and 3 of the left panel.

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Acknowledgements

Acknowledgments This work was supported by grants R01-MH065635, R01-MH074736, NARSAD, the Hirschl Foundation and Philoctetes Foundation awarded to C.M.A., F31-MH816213 to D.Y.C., and T32-MH087004 to S.A.S.; R21-DA29298 and R01-GM054508 to R.D.B. We thank M. Baxter for assistance with statistical analyses. We thank J. Feng, J.-W. Koo and C.-Y. Lu for technical assistance. We thank A. Suzuki and A. Arguello for comments on the manuscript. We thank R. Miller and the Center for Comparative Medicine and Surgery Facility at Mount Sinai School of Medicine for technical support.

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D.Y.C., A.G.-O. and C.M.A. designed and developed this study. D.Y.C., S.A.S. and A.G.-O. carried out the behavioural studies. D.Y.C., A.G.-O., G.P. and D.B.-M. carried out the biochemical studies and analyses. R.D.B. and B.S.-R. designed and conducted the electrophysiology experiments. D.Y.C. and C.M.A. wrote the manuscript.

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Correspondence to Cristina M. Alberini.

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Patent pending on IGF-II as a strategy to enhance memory.

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The file contains Supplementary Figures 1-12 with legends and Supplementary Tables 1-6. This file was replaced on 17 October 2011. (PDF 612 kb)

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Chen, D., Stern, S., Garcia-Osta, A. et al. A critical role for IGF-II in memory consolidation and enhancement. Nature 469, 491–497 (2011). https://doi.org/10.1038/nature09667

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