Abstract
Upon retrieval, fear memories are rendered labile and prone to modification, necessitating a restabilization process of reconsolidation to persist further. This process is also crucial for modulating both strength and content of an existing memory and forms a promising therapeutic target for fear-related disorders. However, the molecular and cellular mechanism of adaptive reconsolidation still remains obscure. Here we show that retrieval of fear memory induces a biphasic temporal change in GluA2-containing AMPA-type glutamate receptor (AMPAR) membrane expression and synaptic strength in the mouse dorsal hippocampus. Blockade of retrieval-induced, regulated, GluA2-dependent endocytosis enhanced subsequent expression of fear. In addition, this blockade prevented the loss of fear response after reconsolidation-update of fear memory content in the long-term. Thus, endocytosis of GluA2-containing AMPARs allows plastic changes at the synaptic level that exerts an inhibitory constraint on memory strengthening and underlies the loss of fear response by reinterpretation of memory content during adaptive reconsolidation.
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Acknowledgements
The authors thank J. Peters, M. van den Oever, R. van Kesteren and S.A. Kushner for critical reading of previous versions of this manuscript, and K.W. Li for technical advice in relation to biotinylation experiments. P.R.-R. was supported by a Neuromics Marie Curie Early Stage Training grant (MEST-CT-2005-020919).
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P.R.-R., A.B.S. and S.S. designed the molecular experiments. P.R.-R., D.C.R., H.D.M. and S.S. designed the physiological experiments. P.R.-R., O.S. and S.S. designed the behavioral experiments. P.R.-R. executed molecular experiments. D.C.R. executed physiological experiments. P.R.-R. and R.J.v.d.L. executed behavioral experiments. P.R.-R. and S.S. analyzed molecular experiments. D.C.R. and H.D.M. analyzed physiological experiments. P.R.-R. and S.S. analyzed behavioral experiments. P.R.-R., D.C.R., A.B.S. and S.S. wrote the manuscript.
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Rao-Ruiz, P., Rotaru, D., van der Loo, R. et al. Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear. Nat Neurosci 14, 1302–1308 (2011). https://doi.org/10.1038/nn.2907
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DOI: https://doi.org/10.1038/nn.2907
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