Protein kinase M (PKM) is a newly described form of PKC that is necessary and sufficient for the maintenance of hippocampal long term potentiation (LTP) and the persistence of memory in Drosophila. PKM is the independent catalytic domain of the atypical PKC isoform and produces long term effects at synapses because it is persistently active, lacking autoinhibition from the regulatory domain of PKC. PKM has been thought of as a proteolytic fragment of PKC. Here we report that brain PKM is a new PKC isoform, synthesized from a PKM mRNA encoding a PKC catalytic domain without a regulatory domain. Multiple -specific antisera show that PKM is expressed in rat forebrain as the major form of in the near absence of full-length PKC. A PKC knockout mouse, in which the regulatory domain was disrupted and catalytic domain spared, still expresses brain PKM, indicating that this form of PKM is not a PKC proteolytic fragment. Furthermore, the distribution of brain PKM does not correlate with PKC mRNA but instead with an alternate RNA transcript thought incapable of producing protein. In vitro translation of this RNA, however, generates PKM of the same molecular weight as that in brain. Metabolic labeling of hippocampal slices shows increased de novo synthesis of PKM in LTP. Because PKM is a kinase synthesized in an autonomously active form and is necessary and sufficient for maintaining LTP, it serves as an example of a link coupling gene expression directly to synaptic plasticity. LTP1 is a persistent enhancement of synaptic transmission widely studied as a physiological model of memory (1). LTP can be divided into two phases: induction, which triggers the potentiation, and maintenance, which sustains it over time. Many molecules have been implicated in LTP induction, which is initiated by the activation of N-methyl-D-aspartate (NMDA) receptors and involves several protein kinases (2). In contrast, very little is known about the molecular mechanism of maintenance. Recently, however, a specific, autonomously active form of the atypical PKC isozyme (3, 4), PKM, has been found both necessary and sufficient for maintaining LTP (5-7). Overexpression of PKM also prolongs memory in Drosophila melanogaster, suggesting it is part of an evolutionarily conserved molecular mechanism for memory storage (8).The unique role of PKM in LTP maintenance is due, in part, to its unusual structural and enzymatic properties as an autonomously active kinase. PKM consists of the independent catalytic domain of a PKC isoform (5). PKC isoforms are divided into three classes: conventional, novel, and atypical (reviewed in Refs. 9 -11). Each isoform is a single polypeptide consisting of an N-terminal regulatory domain and a C-terminal catalytic domain linked by a hinge (Fig. 1A, left). The regulatory domain contains binding sites for second messengers and an autoinhibitory pseudosubstrate sequence, which interacts with and blocks the active site of the catalytic domain. Second messengers stimulate PKC by binding to the regulatory domain, translocating th...

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI: http://dx.doi.org/10.7554/eLife.14846.001

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.