Karim Nader and the unification of memory erasure: PKMζ inhibition and reconsolidation blockade

Abstract

Karim Nader is rightly celebrated for his seminal studies on memory reconsolidation. This commentary celebrates another related contribution - his work on memory maintenance by the autonomously active PKC isoform, PKMζ. There are two methods for "erasing" previously established long-term memory maintenance: 1) inhibiting PKMζ, and 2) blocking reconsolidation. Prior to Nader's research on PKMζ, these two forms of memory erasure were thought to be fundamentally different. Inhibiting PKMζ in a brain region disrupts memory held in storage. But if the inhibitor is injected into the same region immediately after memory retrieval, the drug has no effect. Conversely, inhibiting protein synthesis immediately after memory retrieval blocks reconsolidation. But protein synthesis inhibitors have no effect on memory held in storage without retrieval. The work of Paolo Virginia Migues, Nader, and colleagues, however, revealed an unexpected link between the mechanisms of memory maintenance by PKMζ and the kinase's regulation of postsynaptic AMPAR trafficking that potentiates synaptic transmission and expresses memory during retrieval. This insight led Matteo Bernabo, Nader, and colleagues to observe that memory retrieval first rapidly degrades PKMζ, and then induces the resynthesis of the kinase to restore maintenance of the retrieved memory. This finding explains why a PKMζ inhibitor such as ZIP, if injected in a brain region storing a memory, does not erase the memory immediately after retrieval - the kinase maintaining the retrieved memory has been degraded but not yet resynthesized. Moreover, Bernabo et al. showed that suppressing the resynthesis of PKMζ after its degradation prevents memory reconsolidation, reproducing the effect of general protein synthesis inhibition. Thus, Nader and colleagues demonstrated PKMζ inhibition and reconsolidation blockade disrupt in different ways the same molecular mechanism of memory maintenance - PKMζ inhibition erases all memories maintained in storage by the kinase; reconsolidation blockade disrupts specific recalled memories maintained by PKMζ by preventing resynthesis of the kinase after its degradation.

Keywords: LTP; Long-term potentiation; PKM-zeta; PKMzeta; ZIP; Zeta-inhibitory peptide.

Figure 1.

The erasure of stored long-term memory by PKMζ inhibition and reconsolidation blockade disrupt the same molecular mechanism of memory maintenance. Information encoding a memory is consolidated by new protein synthesis of PKMζ, a persistently active kinase. General protein synthesis inhibitors such as anisomycin or the specific PKMζ synthesis inhibitor PKMζ-antisense prevent consolidation. PKMζ protein or activity inhibitors such as ZIP, chelerythrine, dominant-negative mutated-PKMζ, or PKMζ-RNAi disrupt downstream mechanisms of synaptic potentiation and all memories held in storage by the persistent action of the kinase (Pastalkova et al., 2006; Serrano et al., 2008; Shema et al., 2011; Wang et al., 2016). Recall downregulates PKMζ maintaining the specific retrieved memory by proteolytic degradation, which is followed by resynthesis of the kinase during memory reconsolidation. Anisomycin (Nader et al., 2000a) or PKMζ-antisense (Bernabo et al., 2021) prevent the resynthesis of PKMζ and therefore erase maintenance of the specific retrieved memory.