PKMζ‐knockout mice lack neocortical long‐term potentiation: limits of hippocampal compensation and differential memory rescue

Are there fundamental molecular mechanisms maintaining long-term memory? Memory is thought to be stored by the persistent strengthening of synapses that maintain the networks of neurons encoding experience-dependent information. This persistent strengthening is reproduced during long-term potentiation (LTP), in which strong afferent synaptic stimulation triggers the sustained enhancement of the active synapses. The leading candidate for a ‘memory molecule’ maintaining both LTP and long-term memory is protein kinase Mzeta (PKMζ), a persistently active, neural-specific, atypical protein kinase C (PKC) isoform (Tsokas et al., 2024). PKMζ potently enhances synaptic transmission and is continually targeted to active synapses by interactions with another memory molecule, the postsynaptic scaffolding protein, KIBRA (kidney and brain protein), which is genetically linked to human memory performance (Tsokas et al., 2024). Inhibitors of PKMζ activity or its targeting to KIBRA, as well as shRNA directed against PKMζ-mRNA, can uniquely reverse established LTP or disrupt long-term memory even weeks after learning (Tsokas et al., 2024; Wang et al., 2016). PKMζ-knockout mice revealed that other PKCs can also maintain LTP and memory to compensate for the loss of PKMζ (Tsokas et al., 2016). The initial studies of compensation for LTP were performed in the hippocampus where memory is first formed and stored. In wild-type mice PKMζ-antisense oligodeoxynucleotides and inhibitors of the kinase's alignment at active synapses prevent hippocampal late LTP, but these agents have no effect on hippocampal LTP in PKMζ-knockout mice (Tsokas et al., 2024; Tsokas et al., 2016). LTP and memory in PKMζ-knockout mice might be restored by the prolonged action of PKCiota/lambda (ι/λ), which converts from a transiently active to persistently active form (Tsokas et al., 2016; Wang et al., 2016). In PKMζ-knockout mice simple tasks appear normal (Volk et al., 2013); however cognitively demanding tasks are impaired, indicating the compensation is incomplete (Tsokas et al., 2016). Some evidence suggests that a double knockout of both PKMζ and PKCι/λ eliminates LTP in the hippocampus and the ability to perform simple tasks (Tsokas et al., 2025). Kniffin et al. (2025) may now help explain how PKMζ-knockout mice with compensated LTP in the hippocampus nonetheless fail to perform complex tasks. The authors examined the neocortex where memories are thought to be permanently stored, studying LTP in a region called the medial prefrontal cortex (mPFC) that plays an important role in discriminating between closely related memories (Fig. 1A). They found that unlike the LTP that is compensated in the hippocampus of PKMζ-knockout mice, LTP in the mPFC of mutant mice is eliminated (Kniffin et al., 2025). How is PKMζ’s function in LTP maintenance restored in the hippocampus and not in the neocortex? One possibility is that the putative compensatory mechanism of the hippocampus – the persistent action of PKCι/λ – is not present in the neocortex. In the hippocampus of wild-type mice, blocking PKMζ disrupts late LTP but not early LTP (Tsokas et al., 2024; Tsokas et al., 2016; Wang et al., 2016). In contrast in the mPFC of PKMζ-knockout mice, the loss of PKMζ disrupts both early- and late LTP (Fig. 1A). The mPFC thus appears to lack the ability to upregulate or correctly compartmentalize PKCι/λ, either in early LTP or as a ‘back-up’ maintenance mechanism in the absence of PKMζ. Long-term depression in mPFC is also lost in the knockout. This suggests that PKMζ action, which potentiates synaptic transmission by increasing the number of postsynaptic AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors), is a prerequisite for removal of the receptors during synaptic depression. The lack of LTD in the ζ-knockout raises the possibility that a pre-existing synaptic potentiation related to late LTP may have occurred in mPFC, perhaps at an earlier stage of development. If Kniffin's findings extend to other neocortical regions, PKMζ-knockout mice might be a unique tool to study the differential roles of hippocampal and neocortical LTP in memory. PKMζ-knockout mice can perform simple tasks such as recognizing that an object in a familiar place has been moved to a new location (Fig. 1B) (Tsokas et al., 2016). Memory for the original place is necessary to recognize the novel location, which is measured by the mouse spending more time exploring the object in the novel place. This is like recognizing that a fork left in one's bedroom is not where it should be. But PKMζ-knockout mice cannot perform the more difficult task of recognizing two objects that have exchanged places, which wild-type mice do well. This object–place mismatch is like recognizing that the positions of the knife and spoon on a place setting have been switched. The PKMζ-knockout mice suggest that hippocampal LTP, even in a compensated form, may be sufficient to perform the simple task, but mPFC LTP might be necessary to remember the more complex task. Thus by failing to compensate in the neocortex, PKMζ-knockout mice could reveal what hippocampal LTP by itself can do. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. T.C.S.: conception and design of the work; drafting the work and revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. HHS | NIH | National Institute of Mental Health (NIMH): Todd C. Sacktor, MH115304; HHS | NIH | National Institute of Mental Health (NIMH): Todd C. Sacktor, 2R37MH057068.