These interesting results are consistent with a large body of previous research showing that PKC is involved in associative learning and memory. Much of the previous research dating back to the 1980s focused on conventional and novel PKC isoforms, showing that PKCα and ε are activated and translocated to dendritic membranes after associative learning (1-3). PKC activators have also been found to have therapeutic benefits for Alzheimer's disease transgenic mice, reducing Aβ and increasing the number of mushroom spine synapses (4).

PKMζ, the isoform studied here, is an N-terminal truncated form of PKCζ which lacks the auto-inhibitory regulatory domain of the parent protein and contains only the catalytic domain (5). This makes it different from other forms of PKC by being constitutively active in the absence of the normal PKC signaling molecules (mainly calcium and diacylglycerol). Since PKMζ lacks most of the other isoforms' capacity for physiological regulation, it must function in an entirely different mode. The article by Shema et al. shows that PKMζ seems to enhance the...  Read more

These interesting results are consistent with a large body of previous research showing that PKC is involved in associative learning and memory. Much of the previous research dating back to the 1980s focused on conventional and novel PKC isoforms, showing that PKCα and ε are activated and translocated to dendritic membranes after associative learning (1-3). PKC activators have also been found to have therapeutic benefits for Alzheimer's disease transgenic mice, reducing Aβ and increasing the number of mushroom spine synapses (4).

PKMζ, the isoform studied here, is an N-terminal truncated form of PKCζ which lacks the auto-inhibitory regulatory domain of the parent protein and contains only the catalytic domain (5). This makes it different from other forms of PKC by being constitutively active in the absence of the normal PKC signaling molecules (mainly calcium and diacylglycerol). Since PKMζ lacks most of the other isoforms' capacity for physiological regulation, it must function in an entirely different mode. The article by Shema et al. shows that PKMζ seems to enhance the learned response in taste-aversion conditioning. However, the authors also found that it enhanced the response to a weak aversive stimulus, whether it was given before training or after consolidation.

What do these results mean? One possibility is that PKMζ is somehow involved in heightening of the salience or the response component of the taste aversion response. This could explain how it can enhance multiple taste associations given at different times. Alternatively, PKMζ might be continuously required to maintain the strength of previously consolidated memories. This would imply that a constant input of energy (as ATP) is required to prevent forgetting. In the absence of kinase activity, there must be endogenous phosphatases that automatically and non-specifically erase consolidated memories. If this is so, much challenging work lies ahead as researchers discover how this system could enhance memories while still maintaining the learning-required stimulus specificity of distinct associations stored in long-term memory.

References:
1. Bank B, DeWeer A, Kuzirian AM, Rasmussen H, Alkon DL. Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1988-92. Abstract

2. Olds JL, Anderson ML, McPhie DL, Staten LD, Alkon DL. Imaging of memory-specific changes in the distribution of protein kinase C in the hippocampus. Science. 1989 Aug 25;245(4920):866-9. Abstract

3. Pasinelli P, Ramakers GM, Urban IJ, Hens JJ, Oestreicher AB, de Graan PN, Gispen WH. Long-term potentiation and synaptic protein phosphorylation. Behav Brain Res. 1995 Jan 23;66(1-2):53-9. Abstract

4. Hongpaisan J, Sun MK, Alkon DL. PKC ε activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci. 2011 Jan 12;31(2):630-43. Abstract

5. Sacktor TC. How does PKMζ maintain long-term memory? Nat Rev Neurosci. 2011 Jan;12(1):9-15. Abstract

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View all comments by Thomas Nelson

This study reports that learning in rats prompts their hippocampal astrocytes to release lactate, which is critical for retaining the acquired memories. Although memory formation has previously been shown to involve a myriad of generic metabolites, one exciting aspect of this paper is that it associates learning with the boost of astrocytic lactate release as an essential condition for downstream cascades in neurons (which are classically attributed to learning and memory). Furthermore, the enhanced lactate release appears important for long-term rather than short-term memory formation. Does this imply that astroglia receive a warning signal about long-term importance of a particular learning process before the memories are actually formed?

The results show that adding exogenous lactate could rescue memory impairment consequent to an interruption of astrocytic glycogenolysis activity. This suggests that memory loss associated with pathological deficiency in lactate supply might be improved by lactate, but whether such effects could be achieved for other brain dysfunctions...  Read more

This study reports that learning in rats prompts their hippocampal astrocytes to release lactate, which is critical for retaining the acquired memories. Although memory formation has previously been shown to involve a myriad of generic metabolites, one exciting aspect of this paper is that it associates learning with the boost of astrocytic lactate release as an essential condition for downstream cascades in neurons (which are classically attributed to learning and memory). Furthermore, the enhanced lactate release appears important for long-term rather than short-term memory formation. Does this imply that astroglia receive a warning signal about long-term importance of a particular learning process before the memories are actually formed?

The results show that adding exogenous lactate could rescue memory impairment consequent to an interruption of astrocytic glycogenolysis activity. This suggests that memory loss associated with pathological deficiency in lactate supply might be improved by lactate, but whether such effects could be achieved for other brain dysfunctions resulting in memory impairment remains to be seen.

View all comments by Dmitri Rusakov

In this important study, Shema et al. provide evidence that altering the activity of a single kinase in the brain, PKMζ, can have dramatic effects on the maintenance of long-term memory. Previous results from these same authors had reached similar conclusions (Pastalkova et al., 2006; Shema et al., 2007), but the earlier studies used drugs to inhibit PKMζ’s activity, leaving room for skepticism, because drugs can have non-specific effects. In this new study, the authors injected lentiviruses containing either the gene for PKMζ, or the gene for an inhibitory dominant-negative (DN) version of PKMζ, into the insular cortex (IC) of rats six days after the rats had been given conditioned taste aversion (CTA) training. (The IC is known to be the site of storage of the long-term memory for CTA [Yamamoto et al., 1980].) When tested seven days after the injections, rats whose IC contained neurons that overexpressed PKMζ due to viral infection exhibited significantly enhanced avoidance of the aversive taste. By contrast, in rats with IC neurons that overexpressed the DN form of PKMζ, the...  Read more

In this important study, Shema et al. provide evidence that altering the activity of a single kinase in the brain, PKMζ, can have dramatic effects on the maintenance of long-term memory. Previous results from these same authors had reached similar conclusions (Pastalkova et al., 2006; Shema et al., 2007), but the earlier studies used drugs to inhibit PKMζ’s activity, leaving room for skepticism, because drugs can have non-specific effects. In this new study, the authors injected lentiviruses containing either the gene for PKMζ, or the gene for an inhibitory dominant-negative (DN) version of PKMζ, into the insular cortex (IC) of rats six days after the rats had been given conditioned taste aversion (CTA) training. (The IC is known to be the site of storage of the long-term memory for CTA [Yamamoto et al., 1980].) When tested seven days after the injections, rats whose IC contained neurons that overexpressed PKMζ due to viral infection exhibited significantly enhanced avoidance of the aversive taste. By contrast, in rats with IC neurons that overexpressed the DN form of PKMζ, the long-term memory for CTA was disrupted.

Importantly, the present study included several controls for non-specificity of the effects of their genetic manipulations. For example, the authors showed that overexpression of PKMζ in the IC did not affect the innate preference of untrained (naïve) rats for the taste of the substance (saccharin) used as the conditioned stimulus (CS) in CTA training; nor did IC overexpression of PKMζ change the volume of saccharin-laced liquid that rats consumed in the initial phase of CTA training, prior to the injection of lithium chloride (LiCl), the drug used to sicken the rats in the CTA protocol. Thus, the overexpression did not produce sensorimotor effects. The authors also showed that, despite producing enhancement of long-term memory, overexpression of PKMζ did not block normal extinction of CTA memory produced by repeated exposure to the CS. Another interesting finding in the present study is that the injection of the overexpression viral construct enhanced not only the aversive memory for a CS used in CTA training six days before the injection, but also the memory for a different CS used in an earlier round of CTA training eight days before the injection. Therefore, overexpression of PKMζ can enhance the CTA memory of multiple taste associations.

The study by Shema et al.—due to the specificity of the genetic manipulations that were used, together with the inclusion of extensive and appropriate controls—shrinks the room for skepticism regarding the importance of PKMζ in maintaining at least some forms of long-term memory to a vanishing point. Nonetheless, several key questions remain. Does altering PKMζ’s activity facilitate or disrupt general retrieval processes (“item-invariant” memory operations in the authors’ term), or does it strengthen or weaken specific stored memories (through “item-variant” memory operations)? The authors prefer the latter interpretation, but the data in their study do not decide the issue. Also, is PKMζ required for the maintenance of all long-term memories? Apparently not, because inhibition of PKMζ does not disrupt the retention of some forms of long-term memory (Shema et al., 2007; Serrano et al., 2008; Kwapis et al., 2009). What, then, are the other key memory-maintaining molecules? Finally, and most importantly, if PKMζ is indeed a key molecule for memory maintenance, as the present study indicates, exactly how does its activity mediate the persistence of specific memories? Some work has been done on this critical question. Sacktor and his colleagues have shown that PKMζ activity maintains GluR2 subunit-containing 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptors in the post-synaptic membrane of recently potentiated synapses (Migues et al., 2010). However, PKMζ may mediate memory persistence through other mechanisms. For example, long-term memory is known to involve structural changes in the nervous system (Bailey and Kandel, 1993). Might PKMζ’s activity play a role in the maintenance of these changes?

The results in the present study proffer the hope that we will one day be able to modify long-term memories. Such modification holds out hope for treatment of such memory-related disorders as Alzheimer’s disease, post-traumatic stress disorder, and drug addiction. The technology of memory modification is still a long way off, however. The development of this technology will require that we answer the questions outlined above, as well as develop the means to physically identify specific engrams in the human brain (see Han et al., 2007). Nonetheless, the study by Shema et al. represents a major step toward the eventual goal of manipulating long-term memory.

References:
Bailey CH, Kandel ER (1993) Structural changes accompanying memory storage. Annu Rev Physiol 55:397-426. Abstract

Han JH, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ, Josselyn SA (2007) Neuronal competition and selection during memory formation. Science 316:457-460. Abstract

Kwapis JL, Jarome TJ, Lonergan ME, Helmstetter FJ (2009) Protein kinase Mzeta maintains fear memory in the amygdala but not in the hippocampus. Behav Neurosci 123:844-850. Abstract

Migues PV, Hardt O, Wu DC, Gamache K, Sacktor TC, Wang YT, Nader K (2010) PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci 13:630-634. Abstract

Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC (2006) Storage of spatial information by the maintenance mechanism of LTP. Science 313:1141-1144. Abstract

Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA (2008) PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol 6:2698-2706. Abstract

Shema R, Sacktor TC, Dudai Y (2007) Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMzeta. Science 317:951-953. Abstract

Yamamoto T, Matsuo R, Kawamura Y (1980) Localization of cortical gustatory area in rats and its role in taste discrimination. J Neurophysiol 44:440-455. Abstract

View all comments by David Glanzman