Mechanism for long-term memory formation when synaptic strengthening is impaired

Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-defi...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (45), p.18471-18475
Main Authors: Radwanska, Kasia, Medvedev, Nikolay I, Pereira, Grace S, Engmann, Olivia, Thiede, Nina, Moraes, Marcio F. D, Villers, Agnes, Irvine, Elaine E, Maunganidze, Nicollette S, Pyza, Elżbieta M, Ris, Laurence, Szymańska, Magda, Lipiński, Michał, Kaczmarek, Leszek, Stewart, Michael G, Giese, K. Peter
Format: Article
Language:English
Subjects:
Actinomycin
Animals
Behavioral neuroscience
Biological Sciences
Brain
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Disks Large Homolog 4 Protein
gene expression regulation
Genes, Immediate-Early
Genotypes
Guanylate Kinases - pharmacology
Hippocampus
Hippocampus - metabolism
Long term potentiation
Membrane Proteins - pharmacology
Memory
Memory, Long-Term
Mice
mutants
Mutation
Neuroscience
Phosphorylation
Proteins
Signal transduction
Sirolimus - pharmacology
synapse
Synapses
Synapses - physiology
TOR Serine-Threonine Kinases - metabolism
Up regulation
Up-Regulation - drug effects
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Summary:Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1109680108