The role of nuclear PKMζ in memory maintenance

Ko, Hyoung‐Gon; Kim, Ji Il; Sim, Su Eon; Kim, Tae Hyun; Yoo, Juyoun; Choi, Sun Lim; Baek, Sung Hee; Yu, Won Jin; Yoon, Jong Bok; Kaang, Bong Kiun

doi:10.1016/j.nlm.2016.06.010

Cited by 22 publications

(25 citation statements)

References 32 publications

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“…Several putative mechanisms for maintaining PKMζ have been proposed, including positive feedback loops at the levels of PKMζ mRNA transcription (Chen et al, 2014; Hernandez et al, 2014; Ko et al, 2016), translation of the PKMζ message (Fiumara et al, 2015; Jalil, Sacktor, & Shouval, 2015; Westmark et al, 2010), and PKMζ protein stability (Sacktor, 2011). How these mechanisms become engaged during memory formation and thus sustain PKMζ during memory maintenance are fundamental questions for elucidating how memories are stored.…”

Section: Discussionmentioning

confidence: 99%

Persistent increased PKMζ in long-term and remote spatial memory

Hsieh

Tsokas

Serrano

et al. 2017

Neurobiology of Learning and Memory

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PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase’s action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1 day to 1 month after training. Therefore, if the mechanisms of PKMζ’s persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1 day to 1 month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase’s action during long-term and remote spatial memory maintenance.

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Section: Discussionmentioning

confidence: 99%

Persistent increased PKMζ in long-term and remote spatial memory

Hsieh

Tsokas

Serrano

et al. 2017

Neurobiology of Learning and Memory

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“…PKMζ may act both upstream and downstream in these epigenetic mechanisms. Phosphorylation by nuclear PKMζ maintains histone acetylation during memory storage (59), and decreased DNA methylation of the Prkcz gene after memory formation leads to increase amounts of PKMζ mRNA (60). How might the epigenetic regulation of PKMζ and the nuclear effects of PKMζ interact with its role in synaptic potentiation?…”

Section: Discussionmentioning

confidence: 99%

The genetics of PKMζ and memory maintenance

Sacktor

Hell

2017

Sci. Signal.

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Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mζ (PKMζ) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMζ has been challenged by genetic data from PKMζ-knockout mice showing intact LTP and long-term memory. Moreover, the PKMζ inhibitor peptide ζ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice. Data from four papers using additional isoform-specific genetic approaches have helped to reconcile these conflicting findings. First, a PKMζ-antisense approach showed that LTP and longterm memory in PKMζ-knockout mice are mediated through a compensatory mechanism that depends on another ZIP-sensitive atypical isoform, PKCι/λ. Second, short hairpin RNAs decreasing the amounts of individual atypical isoforms without inducing compensation disrupted memory in different temporal phases. PKCι/λ knockdown disrupted short-term memory, whereas PKMζ knockdown specifically erased long-term memory. Third, conditional PKCι/λ knockout induced compensation by rapidly activating PKMζ to preserve short-term memory. Fourth, a dominant-negative approach in the model system Aplysia revealed that multiple PKCs form PKMs to sustain different types of long-term synaptic facilitation, with atypical PKM maintaining synaptic plasticity similar to LTP. Thus, under physiological conditions, PKMζ is the principal PKC isoform that maintains LTP and long-term memory. PKCι/λ can compensate for PKMζ, and because other isoforms could also maintain synaptic facilitation, there may be a hierarchy of compensatory mechanisms maintaining memory if PKMζ malfunctions.

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“…3A). A mixed ANOVA showed significant effects of the sessions [F (3,36) Fig. 3B, there were significant differences between control and ZIP groups (n = 7 in both cases) during Test A 2 (P = 0.0001; g = 2.53), and Test A 3 (P = 0.0001; g = 4.11), but not the reactivation session (P = 0.99; g = 0.13) or Test A 1 (P = 0.54; g = 1.35).…”

Section: Effects Of Pl Cortex Pkmζ Inhibition By Zip On the Persistenmentioning

confidence: 99%

“…The role of each one of these PKC isoforms is currently under investigation. Accumulating evidence suggests that persistent activation of an atypical protein kinase C isoform (PKMζ) at the late phase of memory consolidation is responsible for maintaining long-term potentiation and long-term memory [3][4][5] . PKMζ has also been reported to be necessary for the persistence of newly acquired procedural, spatial, appetitive (rewarding), and aversive memories 4,[6][7][8] .…”

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Role of prelimbic cortex PKC and PKMζ in fear memory reconsolidation and persistence following reactivation

Silva

Raymundi

Bertoglio

et al. 2020

Sci Rep

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the persistence of newly acquired memories is supported by the activity of pKMζ, an atypical isoform of protein kinase c (pKc). Whether the activity of conventional and atypical pKc isoforms contributes to reactivated memories to persist is still unknown. Similarly, whether memory reactivation is a prerequisite for interventions to be able to change memory persistence is scarcely investigated. Based on the above, we examined the role of conventional and atypical pKc isoforms in the prelimbic cortex in reconsolidation and persistence of a reactivated contextual fear memory in male Wistar rats. it is shown that (i) inhibiting the pKc activity with chelerythrine or the pKMζ activity with Zip impaired the persistence of a reactivated memory for at least 21 days; (ii) ZIP given immediately after memory reactivation affected neither the reconsolidation nor the persistence process. In contrast, when given 1 h later, it impaired the memory persistence; (iii) chelerythrine given immediately after memory reactivation impaired the reconsolidation; (iv) omitting memory reactivation prevented the chelerythrine-and ZIP-induced effects: (v) the ZIP action is independent of the time elapsed between its administration and the initial memory test. the results indicate that prelimbic cortex pKc and pKMζ are involved in memory reconsolidation and persistence.

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The role of nuclear PKMζ in memory maintenance

Cited by 22 publications

References 32 publications

Persistent increased PKMζ in long-term and remote spatial memory

Persistent increased PKMζ in long-term and remote spatial memory

The genetics of PKMζ and memory maintenance

Role of prelimbic cortex PKC and PKMζ in fear memory reconsolidation and persistence following reactivation

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