How the brain stores information is a question that has fascinated neuroscientists for well over a century. Two general ideas have emerged. The first is that groups of neurons hold information by staying active. The second is that they hold information by strengthening their connections to one another, making it easier for them to work together in the future. Scientists call this second idea 'long-term potentiation'.

One of the molecules involved in long-term potentiation is a protein called calcium-calmodulin-dependent kinase II, or CaMKII for short. Blocking CaMKII, or deleting its gene, stops the connections between neurons from becoming stronger. This suggests neurons need CaMKII to learn, but it remains unclear whether neurons also use CaMKII to maintain neuronal memories after they have been created. If CaMKII does play a role in maintaining memories, blocking it after learning should reverse the learning process, but so far, experiments have not been able to show this.

Tao et al. revisited these experiments to find out more. They examined slices of brain tissue from mice that had been treated with fast-acting CaMKII inhibitors. It took tens of minutes, but the inhibitors were able to reverse long-term potentiation, both for newly acquired neuronal memories and for older memories that had formed when the mice were alive. The choice of CaMKII inhibitor and the time lag could explain why scientists have not observed the effect before.

Understanding long-term potentiation is a fundamental part of understanding learning and memory. It could also reveal more about the opposite phenomenon: long-term depression. This is a type of learning where the connections between neurons become weaker. Long-term depression also takes tens of minutes to occur, suggesting that future research into CaMKII might shed light on how it works.

The mechanism by which the brain stores information has fascinated neuroscientists for well over a century. Two general ideas have emerged. The first proposes that information is held by ongoing activity in neuron ensembles. This, indeed, underlies short-term working memory (D’Esposito and Postle, 2015; Inagaki et al., 2019; Wang, 2001). However, it is clear that such a mechanism cannot account for long lasting, enduring memories. For instance, it is well established that patients who recover from prolonged periods of isoelectric EEG and brain stem silence following barbiturate overdose have no detectable cognitive deficits, for example, Bird and Plum, 1968. The second and generally accepted view, first enunciated by Cajal over a century ago (Cajal, 1911), is the modification of neuronal connections. How these changes might be stored has remained a mystery.

Over the past few decades, Ca²⁺-calmodulin-dependent kinase II (CaMKII) has emerged as a very attractive molecular candidate for information storage (Bayer and Schulman, 2019; Bhattacharyya et al., 2020; Hell, 2014; Kennedy, 2013; Lisman et al., 2002; Lisman et al., 2012; Lisman and Goldring, 1988). This dodecameric kinase is activated by Ca²⁺/CaM resulting in autophosphorylation and the activity of the kinase remains after the removal of Ca²⁺ (Miller and Kennedy, 1986), a state referred to as autonomy. Furthermore, evidence suggests that the enzyme can undergo activation-triggered subunit exchange such that subunits that did not experience the original Ca²⁺ transient are phosphorylated, a mechanism postulated to allow for continued phosphorylation in the face of protein turnover (Bhattacharyya et al., 2020; Bhattacharyya et al., 2016; Stratton et al., 2014) Thus, CaMKII has many attractive biochemical features expected for a memory molecule. What is the physiological evidence for such a role?

Long-term potentiation (LTP), in which brief high-frequency synaptic stimulation results in a lasting increase in synaptic strength, is an attractive cellular model for learning and memory (Choquet, 2018; Collingridge et al., 2004; Huganir and Nicoll, 2013; Malinow and Malenka, 2002; Nicoll, 2017). A role for CaMKII in LTP is compelling. Pharmacologically blocking CaMKII (Malenka et al., 1989; Malinow et al., 1989; Otmakhov et al., 1997) or genetically deleting CaMKII (Giese et al., 1998; Incontro et al., 2018; Silva et al., 1992) blocks LTP and constitutively active CaMKII both mimics and occludes LTP (Lledo et al., 1995; Pettit et al., 1994; Pi et al., 2010; Poncer et al., 2002). However, despite the attractive biochemical properties of CaMKII, whether CaMKII is involved in the maintenance of LTP and, by extension, memory storage remains problematic.

There are two predictions if CaMKII is responsible for LTP maintenance and synaptic memory (Lisman, 2017; Sanhueza and Lisman, 2013). First, transiently blocking CaMKII after the induction of LTP should cause a long-lasting erasure. Attempts at reversing LTP have failed on numerous occasions (Buard et al., 2010; Chen et al., 2001; Malinow et al., 1989; Murakoshi et al., 2017; Otmakhov et al., 1997), but see Feng, 1995. Second, if CaMKII is involved in synaptic memory, one would expect it to leave a lasting trace at synapses (Lisman, 2017; Sanhueza et al., 2011; Sanhueza and Lisman, 2013). Thus, silencing CaMKII should reduce synaptic transmission. Interestingly, the CaMKII/NMDAR complex does exist under basal conditions (Leonard et al., 1999). However, the genetic deletion of CaMKII (Achterberg et al., 2014; Giese et al., 1998; Silva et al., 1992), but see Hinds et al., 1998, or pharmacological inhibition of CaMKII does not affect baseline synaptic responses (Buard et al., 2010; Chen et al., 2001; Feng, 1995; Malinow et al., 1989; Murakoshi et al., 2017; Otmakhov et al., 1997; Wang and Kelly, 1996). Finally, using a FRET-based CaMKII sensor, CaMKII activation in spines after LTP induction persists for only ~1 min (Lee et al., 2009). Thus, physiological support for a role of CaMKII in maintaining LTP or synaptic transmission is lacking.

Recent findings have prompted us to reevaluate CaMKII’s role in the maintenance of LTP. Deleting CaMKII with CRISPR (Incontro et al., 2018) or expressing a peptide inhibitor of CaMKII (Goold and Nicoll, 2010; Sanhueza et al., 2011) cause a substantial reduction in synaptic transmission. Furthermore, studies using a membrane permeable peptide inhibitor of CaMKII (tatCN21 or antCN27) have reported a lasting depression in synaptic transmission (Barcomb et al., 2016; Gouet et al., 2012; Sanhueza et al., 2011; Sanhueza et al., 2007) and evidence for a reduction in LTP maintenance (Sanhueza et al., 2011; Sanhueza et al., 2007).

To reevaluate the role of CaMKII in synaptic memory we have used two different rapidly acting and reversible CaMKII inhibitors. As would be expected if LTP contributes to synaptic memory, inhibition of CaMKII depresses synaptic transmission and the properties of this persistent action of CaMKII are remarkably similar to those of LTP. Furthermore, we demonstrate that applying these inhibitors after inducing LTP fully reverses LTP, indicating that CaMKII is required for the persistence of LTP. Thus, our findings strongly support CaMKII as a molecular storage device. Reasons for why the present results differ from most previous studies are discussed.

The role of CaMKII in the maintenance of LTP and information storage has been one of the most vexing issues in the field of synaptic plasticity. On the one hand, the biochemical properties of CaMKII have for decades made this molecule an extremely attractive candidate for molecular storage (Bhattacharyya et al., 2020; Coultrap and Bayer, 2012; Hell, 2014; Lisman et al., 2002; Lisman et al., 2012). On the other hand, numerous physiological experiments over the years have failed to support the role of CaMKII in the maintenance of LTP and by extension memory. To reevaluate the physiological role of CaMKII in synaptic memory, we have used two classes of CaMKII inhibitory peptides. With these inhibitors we find that CaMKII is required for the maintenance of LTP and provide evidence that LTP acquired while the animal was alive leaves a lasting synaptic memory trace.

The first class of inhibitory peptide we used is derived from an endogenous CaMKII inhibitory protein referred to as CaMKIINtide (CN27) (Chang et al., 1998; Goold and Nicoll, 2010; Pellicena and Schulman, 2014; Vest et al., 2007). The second class of inhibitory peptide is derived from the autoinhibitory domain of CaMKII (Bayer et al., 2001; Leonard et al., 1999). Although these inhibitory peptides were thought to bind to separate sites (S and T sites), recent structural studies of the binding of GluN2B and other interacting peptides to CaMKII indicate that these peptides use similar interactions to bind across the substrate binding pocket of the CaMKII active site (Özden et al., 2020). Thus, at present it is not possible to use these two classes of inhibitors to distinguish between the disruption of GluN2B binding and the blockade of kinase activity. These peptides included a myristoylated version of CN27 (myr-CN27), AIP (myr-AIP) and a recently developed photoactivatable peptide inhibitor (paAIP2) (Murakoshi et al., 2017). Both classes of peptides block kinase activity with high affinity (Chang et al., 2001; Ishida et al., 1998), but also interfere with the binding of CaMKII to GluN2B (Sanhueza et al., 2011; Vest et al., 2007).

Our experiments clearly establish that inhibitory peptides fully reverse LTP. How long is CaMKII responsible for maintaining LTP? Experiments addressing the role of constitutive CaMKII in the maintenance of LTP are constrained by the length of recording; approximately 1 hr for whole cell and a few hours for field potentials. However, if LTP is the substrate for memory, it should leave a lasting memory trace at synapses, acquired while the animal is alive (Lisman, 2017; Sanhueza and Lisman, 2013). A number of studies have reported a lasting depression following transient inhibition of CaMKII (Barcomb et al., 2016; Gouet et al., 2012; Sanhueza et al., 2011; Sanhueza et al., 2007). Furthermore, even under basal conditions, CaMKII is found in isolated PSDs (Petersen et al., 2003; Strack et al., 1997) and synaptic puncta (Bayer et al., 2006) and this is in the autophosphorylated state (Strack et al., 2002; Trinidad et al., 2005). As discussed above all three inhibitory peptides (myr-CN27, myr-AIP, and paAIP2) depress synaptic transmission and this depression requires the presence of CaMKII. A number of trivial explanations, such as ongoing constitutive Ca²⁺ activation of the enzyme, were excluded.

We then focused on the possibility that this constitutive action of CaMKII reflects prior LTP. First, the finding that the inhibition does not affect NMDAR responses is consistent with an LTP mechanism, since LTP preferentially enhances AMPAR responses (reviewed in Nicoll, 2017). Second, there should be no recovery from the transient inhibition of CaMKII, analogous to the resetting of a molecular switch. This is, indeed, the case. Third, cells in which the NMDAR has been deleted embryonically should be devoid of the constitutive activity. Again, this is the case. This is unlikely to be due to the loss of GluN2B subunit, because cells expressing a pore dead NMDAR mutant, in which assembles with GluN2B, had little CaMKII constitutive activity. This finding suggests that non-NMDAR sources of Ca²⁺ in the behaving animal are incapable of triggering CaMKII-dependent enhancement in synaptic transmission. This tight linking of NMDAR sources of Ca²⁺ to CaMKII is critical, because it prevents the degrading of the Hebbian nature of plasticity. Finally, it is well established that LTP is saturable. Thus, if constitutively action CaMKII represents LTP, removing this component should allow for larger LTP. We find that in cells in which CaMKII is transiently blocked LTP is approximately twice as large as in neighboring control cells. Taken together these results suggest that constitutive CaMKII represents LTP acquired at synapses while the animal was alive, thus supporting a role for CaMKII in synaptic memory.

Based on the present results the term ‘basal synaptic transmission’ needs to be reevaluated. It has generally been assumed that the synapses studied in a hippocampal slice, in which much of the afferent drive from multiple inputs have been removed in the slicing, are at a ground ‘basal’ state. The present results indicate that the synaptic currents we measure are actually maintained by a persistent enhancement acquired prior to slicing.

It should be pointed out that the contribution of CaMKII to synaptic transmission is unlikely to be a simple addition to the overall preexisting excitatory drive onto the cell. It has long been argued that such a scenario would be unstable and quickly saturate (Bienenstock et al., 1982; Cooper and Bear, 2012; Fusi et al., 2005; Morrison et al., 2008; Toyoizumi et al., 2014; Turrigiano, 2008). A number of well-established mechanisms exist to maintain stability, including heterosynaptic depression (Scanziani et al., 1996), NMDAR-dependent long-term depression (Malenka and Bear, 2004) and on a longer time scale cell wide homeostasis (Turrigiano, 2008). Thus, it is envisaged that the CaMKII memory trace is embedded in a network of synapses with no overall net change in the excitatory drive onto the cell or network.

It is striking to compare the action of paAIP2 on LTP induction (Murakoshi et al., 2017) and on synaptic transmission (present study). A brief light exposure (~1 min), delivered immediately prior to inducing LTP, is sufficient to prevent LTP (Murakoshi et al., 2017). This finding indicates that the blocking of CaMKII activation by paAIP2 is very rapid. In contrast, the effect on synaptic transmission and the reversal of LTP required 10’s of minutes. What might explain the dramatic difference in the kinetics of inhibition of LTP induction compared to LTP maintenance and constitutive CaMKII? There is a well-accepted sequence of events for the role of CaMKII in the induction of LTP (Coultrap and Bayer, 2012; Hell, 2014; Lisman et al., 2012; Nicoll, 2017). Following NMDAR activation Ca²⁺ binds to CaM, which then binds to CaMKII activating the enzyme. This causes the autophosphorylation of T286 and the translocation of cytosolic CaMKII to the PSD where it binds to the C-tail of GluN2B. It seems reasonable to expect that under baseline conditions much of CaMKII and paAIP2 are freely diffusible in the spine cytoplasm, as are phosphatases. The activation of paAIP2 would quickly inhibit CaMKII autophosphorylation and its recruitment to the PSD and phosphatases would quickly reverse its effect. During baseline transmission and during the maintenance of LTP a fraction of CaMKII is bound to GluN2B. Evidence suggests that the CaMKII/GluN2B complex is protected from phosphatases (Cheriyan et al., 2011; Lisman and Raghavachari, 2015; Mullasseril et al., 2007). Thus, reversing action of this sequestered CaMKII would be more difficult than preventing phosphorylation of cytosolic CaMKII.

The present results could shed light on the underlying mechanism of long-term depression (LTD). Although this topic remains contentious (Collingridge et al., 2010; Dore et al., 2016; Goodell et al., 2017; Lisman and Zhabotinsky, 2001; Malenka and Bear, 2004; Stein et al., 2021; Wong and Gray, 2018), the long-held view is that LTD is mediated by the activation of phosphatases, in particular protein phosphatase 1 (PP1) (Mulkey et al., 1994; Mulkey et al., 1993). One of the limitations to this model is the lack of evidence that synaptic transmission is maintained by kinase activity. Our demonstration that CaMKII maintains synaptic transmission provides a very simple model for LTD, that is, a depotentiation or reversal of this prior LTP. One of the features of LTD is that it takes many minutes for its induction. Our finding that it takes many minutes for CaMKII inhibitors to depress synaptic transmission provides an explanation for this property. A formal model for the interplay between CaMKII and PP1 was proposed some time ago (Lisman and Zhabotinsky, 2001). The absence of LTD in CaMKII knockout mice (Coultrap et al., 2014; Stevens et al., 1994) supports such a model, but does not rule out other models.

What might account for the failure of previous studies to detect a component of synaptic transmission driven by constitutive CaMKII (Achterberg et al., 2014; Buard et al., 2010; Chen et al., 2001; Feng, 1995; Giese et al., 1998; Malinow et al., 1989; Murakoshi et al., 2017; Otmakhov et al., 1997; Silva et al., 1992; Wang and Kelly, 1996), but see Hinds et al., 1998, or to detect a role of constitutive CaMKII in maintaining LTP (Buard et al., 2010; Chen et al., 2001; Malinow et al., 1989; Murakoshi et al., 2017; Otmakhov et al., 1997), but see Feng, 1995? We suggest three factors. The first concerns the duration of peptide application, which in our hands takes 10’s of minutes to act, especially with field potential recording. The second concerns the concentration and time. As discussed above it is more difficult to reverse the constitutive action of CaMKII, than it is to block its activation. Finally, the membrane permeabilizing agent is important. In our hands myristoylation was more effective and specific than the CPP, tat.

In summary our results overcome many of the obstacles that have prevented embracing CaMKII as a molecular storage device. Specifically, our results show that transient inhibition of CaMKII results in a lasting depression of synaptic transmission with properties consistent with the erasure of prior LTP acquired while the animal was alive. Furthermore, the finding that CaMKII inhibition after the induction of LTP reverses LTP establishes its role in LTP maintenance. Thus, these physiological results compliment the rich biochemical literature on CaMKII, making CaMKII a particularly attractive molecular storage device. It is important to note, that our results have focused on LTP and it remains open as to whether CaMKII actually stores memories. Recent experiments (Rossetti et al., 2017) using the viral expression of the catalytically dead CaMKII K42M mutant, presumed to act in a dominant negative manner, support its role in memory.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Wucheng Tao

   1. Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, China
   2. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2577-8161

2. Joel Lee

   Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

   Contribution

   Investigation

   Contributed equally with

   Xiumin Chen

   Competing interests

   No competing interests declared

3. Xiumin Chen

   Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

   Contribution

   Data curation, Investigation, Validation

   Contributed equally with

   Joel Lee

   Competing interests

   No competing interests declared

4. Javier Díaz-Alonso

   Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

   Present address

   Department of Neuroscience, University of California, Irvine, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4980-7441

5. Jing Zhou

   Department of Neurology, University of California, San Francisco, San Francisco, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2809-7097

6. Samuel Pleasure

   Department of Neurology, University of California, San Francisco, San Francisco, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8599-1613

7. Roger A Nicoll

   1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
   2. Physiology, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing

   For correspondence

   roger.nicoll@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6977-4632

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