The genetics of PKMζ and memory maintenance

Todd Charlton Sacktor, Johannes W Hell

Research output: Contribution to journalReview article

15 Citations (Scopus)

Abstract

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 Mz (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 z 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.

Original languageEnglish (US)
Article numberaao2327
JournalScience Signaling
Volume10
Issue number505
DOIs
StatePublished - Nov 14 2017

Fingerprint

Protein Kinases
Long-Term Memory
Maintenance
Data storage equipment
Long-Term Potentiation
Protein Isoforms
Protein Kinase C
Knockout Mice
Short-Term Memory
Genetics
Aplysia
Peptides
Neuronal Plasticity
Neurosciences
Small Interfering RNA
Plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The genetics of PKMζ and memory maintenance. / Sacktor, Todd Charlton; Hell, Johannes W.

In: Science Signaling, Vol. 10, No. 505, aao2327, 14.11.2017.

Research output: Contribution to journalReview article

Sacktor, Todd Charlton ; Hell, Johannes W. / The genetics of PKMζ and memory maintenance. In: Science Signaling. 2017 ; Vol. 10, No. 505.
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