The genetics of PKMζ and memory maintenance

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 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 long-term 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.

Fig. 1.. Two distinct atypical PKCs mediate synaptic potentiation In early LTP and late LTP that allows for compensation in knockout mice.

(A) In one mechanism of early LTP in wild-type mice, NMDAR activation by weak afferent stimulation induces activation of PKCι/λ that potentiates synaptic transmission by enhancing exocytosis of AMPARs through p62 and action on the GluA1 subunit of the AMPAR. (B) In late LTP in wild-type mice, NMDAR activation by strong afferent stimulation induces derepression of PKMζ mRNA, increasing de novo synthesis of PKMζ. PKMζ enhances synaptic transmission by blocking endocytosis of postsynaptic AMPARs by the trafficking protein NSF through action on the GluA2 subunit. (C) In late LTP in PKMζ-knockout mice, the persistent increase in PKCι/λ induced through activity-dependent synthesis of the kinase maintains synaptic potentiation. Whether the mechanism of late LTP synaptic potentiation in PKMζ-knockout mice is the same as early LTP in wild-type mice, as shown, is not known. (D) In early LTP in conditional PKCι/λ-knockout mice, PKMζ mRNA is derepressed more rapidly than in wild-type mice, leading to earlier synthesis of PKMζ. The mechanism of synaptic potentiation in early LTP in PKCι/λ-knockout mice switches from GluA1 exocytosis to blocking endocytosis of postsynaptic AMPARs by the trafficking protein NSF through action on the GluA2 subunit, which is the expression mechanism mediated by PKMζ in late LTP in wild-type mice.