Distinct Roles of PKCι/λ and PKMζ in the Initiation and Maintenance of Hippocampal Long-Term Potentiation and Memory

Wang, Shaoli; Sheng, Tao; Ren, Si-Qiang; Tian, Tian; Lü, Wei

doi:10.1016/j.celrep.2016.07.030

Cited by 48 publications

(62 citation statements)

References 29 publications

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“…The results of the pharmacogenetic analysis of the PKMζ-knockout and the shRNA-mediated knockdown of PKMζ demonstrated that PKMζ is the principal PKC isoform maintaining LTP and long-term memory storage under physiological conditions in wild-type mice (15, 47). However, these findings, together with those from the PKCι/λ conditional knockout mice (49), also revealed that the heterogeneity of PKC isoforms provides flexibility to the molecular mechanisms that sustain the fundamental processes of LTP and memory.…”

Section: Discussionmentioning

confidence: 99%

“…In a second study, Wang et al (47) distinguished between the roles of PKCι/λ and PKMζ in synaptic plasticity and memory by using shRNA to decrease the abundance of the isoforms individually. The viral expression of shRNA in the hippocampus reduced the amount of each isoform by ~60 to 75% without inducing a compensatory change in the other.…”

Section: Specific Functions Of Pkcι/λ and Pkmζ In Ltp And Memorymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Specific Functions Of Pkcι/λ and Pkmζ In Ltp And Memorymentioning

confidence: 99%

The genetics of PKMζ and memory maintenance

Sacktor

Hell

2017

Sci. Signal.

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“…Information at the molecular level can be stored as a persistent increase or decrease in the steady-state level or conformation of a protein. Thus, even though the half-life of PKMz may be days in vivo, as suggested by shRNA (Dong et al, 2015;Wang et al, 2016) and inducible genetic knockdowns (Volk et al, 2013), the steady-state increases of PKMz protein can last a month (Fig. 4) (Hsieh et al, 2017;Gao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage

Hsieh

Tsokas

Grau‐Perales

et al. 2020

Preprint

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PKMz-immunohistochemistry reveals persistent increased PKMz in the hippocampus during (A) LTP maintenance, and (B) spatial long-term memory storage.PKMz is an autonomously active, atypical PKC isoform crucial for maintaining synaptic longterm potentiation (LTP) and long-term memory. Unlike other PKCs that are transiently activated by short-lived second messengers, PKMz is persistently activated by long-lasting increases in the amount of the autonomously active kinase during LTP and long-term memory maintenance. Thus, localizing persistent increases in PKMz might reveal traces of physiological LTP maintenance in the circuitry of the brain during long-term memory storage. Using quantitative immunohistochemistry validated by the lack of staining in PKMz-null mice, we visualized the amount and distribution of PKMz during LTP maintenance and spatial long-term memory storage in the hippocampal formation of wild-type mice. Strong afferent stimulation of Schaffer collateral/commissural fibers inducing LTP maintenance increases PKMz in CA1 pyramidal cells for 2 hours in hippocampal slices. Active place avoidance spatial conditioning increases PKMz in CA1 pyramidal cells of the hippocampal formation from 1 day to at least 1 month. The increases in PKMz coincide with the location of cells marked during long-term memory training by Arc promoter-mediated expression of a fluorescent protein, including at dendritic spines. We conclude that increased PKMz forms persistent traces in CA1 pyramidal cells that are sites of molecular information storage during LTP maintenance and spatial long-term memory.

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“…However, what the maintenance network looks like in mammals is not yet known. Recent studies suggested the atypical PKMζ as well as the CAMKII as important factors in this process . The bx homolog Lmo4 might be a good starting point for a TF.…”

Section: Main Textmentioning

confidence: 99%

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

Kaldun

Sprecher

2019

BioEssays

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Consolidation of long‐term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element‐binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB and downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc.

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Distinct Roles of PKCι/λ and PKMζ in the Initiation and Maintenance of Hippocampal Long-Term Potentiation and Memory

Cited by 48 publications

References 29 publications

The genetics of PKMζ and memory maintenance

The genetics of PKMζ and memory maintenance

Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

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