Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

Kimura, Ryuji; Silva, Alcino J.; Ohno, Minoru

doi:10.1101/lm.1049608

Cited by 40 publications

(37 citation statements)

References 32 publications

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“…Our studies show that αCaMKII autophosphorylation-deficient mutants have impaired extinction and destabilization of LTM after retrieval. These observations indicate that not only formation of new memories but also modification of old memories by new experience during extinction requires the αCaMKII autophosphorylation, which is in agreement with a previous analysis of heterozygous T286A mutants (32). Furthermore, destabilization of LTM after retrieval requires αCaMKII autophosphorylation.…”

Section: Discussionsupporting

confidence: 92%

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

Radwańska

Medvedev

Pereira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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 traininginduced 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.synaptic plasticity | hippocampus | immediate-early gene | reconsolidation A fundamental question in neuroscience concerns the cellular mechanisms that lead to long-term memory (LTM) formation (1-3). It has been shown that LTM formation is associated with and demands strengthening of existing synapses, socalled functional plasticity (3-5), but it may also be linked with a more overt form of structural plasticity, an increase in synapse density (6-9). It is, however, unclear whether de novo synaptogenesis is critical for LTM formation.The participation of synaptogenesis for LTM formation can be investigated when synaptic strengthening is fully blocked. It would be ideal to also block training-induced changes in neuronal excitability that have been implicated in memory formation (10). However, technically this block may not be achievable as, for example, there are distinct types of synaptic strengthening. As a proxy, here we have studied T286A missense mutant mice lacking autophosphorylation at threonine 286 of the α-isoform of calcium/calmodulindependent kinase II (αCaMKII), a major protein of glutamatergic synapses in the forebrain (11). The T286A mutants have fully blocked NMDA receptor-dependent synaptic strengthening at hippocampal CA1 synapses (11-14), and they have impaired regulation of the postburst afterhyperpolarization (AHP) in CA1 pyramidal neurons (15). Accordingly, T286A mutants are deficient in contextual fear conditioning after a single training trial (16). However, after five massed training trials, T286A mutants can form contextual LTM (16) and this type of LTM is hippocampus-dependent (14).Here, we have used T286A mutants as tools to investigate the mechanism of LTM formation when NMDA receptor-dependent synaptic strengthening is blocked. Our study provides evidence that activation of mTOR signaling in the hippocampus, followed by overexpression of PSD95 protein and...

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Section: Discussionsupporting

confidence: 92%

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

Radwańska

Medvedev

Pereira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast to other studies using the CFC paradigm (e.g., Kimura et al 2008;Archbold et al 2010), we saw no spontaneous recovery of the behavioral performance after extinction training. Studies with fear conditioning to a discrete cue identified several factors that affect the resistance of extinction to recovery.…”

Section: Discussioncontrasting

confidence: 99%

The exclusive induction of extinction is gated by BDNF

Kirtley¹,

Thomas²

2010

Learn. Mem.

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We have previously reported that the reconsolidation and extinction of hippocampal-dependent contextual fear memory can be initiated by a single context conditioned stimulus (CS) presentation of either short or long duration, and that both processes require protein synthesis in this brain region. Furthermore, reconsolidation depends on Zif268 activity in this region. Here we show that by infusing a recombinant brain-derived neurotrophic factor (rBDNF) directly into the brain of rats, that high levels of mature BDNF in the hippocampus at retrieval constrain the extinction of the fear memory after prolonged memory recall. We also show after a short CS exposure that reconsolidation was impaired using antisense oligonucleotides targeting Zif268, and that, similarly, reductions in conditioned behavior were observed after prolonged CS presentation when extinction is constrained by high levels of BDNF. This is direct evidence that in the mammalian brain extinction proceeds exclusively after prolonged CS exposure. In addition, that BDNF activity in the hippocampus contributes to a molecular switch for the extinction of hippocampal-dependent memory.

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“…Moreover, aCaMKII has also been implicated in memory extinction. Heterozygous T286A mutants have impaired new learning induced by extinction training, whereas extinctionrelated unlearning is spared (Kimura et al 2008a).…”

Section: Camkiimentioning

confidence: 99%

The roles of protein kinases in learning and memory

2013

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In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate gene expression and protein synthesis causing structural changes at existing synapses as well as synaptogenesis. Here, we review the roles of these kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. Specifically, we discuss the roles of calcium/calmodulin-dependent kinase II (CaMKII

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Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

Cited by 40 publications

References 32 publications

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

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

The exclusive induction of extinction is gated by BDNF

The roles of protein kinases in learning and memory

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