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PI3 kinase signaling is required for retrieval and extinction of contextual memory

Abstract

Memory retrieval is a dynamic aspect of memory formation that can be studied separately from other stages of memory processing. Although several signal transduction pathways including ERK/MAP kinase have been implicated in memory retrieval, the underlying signaling events are poorly defined. Here we report that re-exposure of mice to context after contextual training stimulates the activity of phosphatidylinositol 3 kinase (PI3K) in the hippocampus. Inhibition of PI3K activity in the hippocampus in vivo blocked contextual memory retrieval and extinction. Inhibitors of PI3K signaling also blocked increases in ERK/MAP kinase activity associated with memory retrieval. This suggests that PI3K activation in the hippocampus is critical for memory retrieval and is required for activation of ERK/MAP kinase during retrieval.

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Figure 1: PI3K and ERK/MAPK are activated in the hippocampus during contextual memory retrieval.
Figure 2: PI3K is activated in area CA1, CA3 and dentate gyrus after contextual memory retrieval.
Figure 3: Intrahippocampal administration of LY294002 blocks contextual memory retrieval.
Figure 4: LY294002 infusion suppresses PI3K activity.
Figure 5: PI3K inhibition blocks ERK/MAPK activation during retrieval.
Figure 6: PI3K is required for contextual memory extinction but not for reconsolidation.

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Acknowledgements

We thank members of the Storm lab for constructive reading of the manuscript and editorial input. Microscopy and image analysis was performed in the W.M. Keck Center for Neural Signaling, University of Washington. This research was supported by US National Institutes of Health grants NS20498 and NS37056.

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Correspondence to Daniel R Storm.

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Supplementary information

Supplementary Fig. 1

Cannula tip placements from mice infused with vehicle (open triangle) and LY294002 (closed circle). (PDF 15126 kb)

Supplementary Fig. 2

LY294002 infusion does not affect locomotor activity or acquisition of contextual learning. (PDF 4036 kb)

Supplementary Fig. 3

LY blocks KCl-induced ERK/MAPK activity and CRE-mediated gene expression. (PDF 4130 kb)

Supplementary Fig. 4

Administration of LY to the hippocampus to mice in which contextual memory had been repeatedly retrieved does not block reconsolidation. (PDF 2792 kb)

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Chen, X., Garelick, M., Wang, H. et al. PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nat Neurosci 8, 925–931 (2005). https://doi.org/10.1038/nn1482

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