House of Mind

"Biology gives you a brain. Life turns it into a mind" - Jeffrey Eugenides

  • 25th January
  • 25

PKMzeta Memory Molecule Theory Debunked

2013 started off with a neuroscience bang! Prior to January 2, 2013, the prevailing notion of how long term memories are formed was centered around an enzyme called PKM zeta (also known as PKC zeta). As an enzyme, PKMzeta is special due to its lack of an autoinhibitory regulatory domain, it is constitutively and persistently active- meaning that it is always “ON”. In 2007, Dudai and colleagues demostrated the importance of this enzyme when they were able to erase long term memories in mice by injecting ZIP, a PKMzeta inhibitor, into the hippocampus (i.e. the main structure associated w/ memory formation). Because ZIP mimics the regulatory domain that PKMzeta is missing and turns the enzyme’s activity “OFF” and ZIP administration was enough to erase memory in mice, the consensus in the field was that PKMzeta was required for the creation of new memories. Furthermore, research by other groups provided additional support for this notion by showing that infusion of ZIP was able to eliminate memories for a multitude of experience dependent behaviors such as: fear conditioning, spatial learning, active place avoidance and conditioned taste aversion. 

So what happened? In short, genetics :) Two separate research groups (Huganir lab at Johns Hopkins and the Messing lab at UCSF) used a clever technique known as a genetic knockout to make a strain of mice lacking the gene that produced the PKMzeta enzyme. Basically, these mice had no PKMzeta activity BUT…….

They were still able to learn and create new memories! Not only that, Volk et. al also showed that these knockout mice lacking PKMzeta exhibited normal synaptic activity and long term potentiation (LTP) in the hippocampus as well as normal behavior in hippocampal dependent tasks such as the Morris water maze. Moreover, Lee et. al were able to gather additional evidence that PKMzeta is not integral to memory formation by demonstrating that these knockout mice did not show deficits in tests of: cued fear conditioning, novel object recognition, object location recognition, conditioned place preference, and motor learning when compared to wild type (control) littermates. In sum, these knockout mice showed brain function and behavior comparable to normal mice, suggesting that PKMzeta may not be as important for learning and memory as previously thought. 

Furthermore, the double whammy came about when Volk and colleagues administered ZIP (which was thought to be highly specific to PKMzeta) to both the knockout mice and the normal mice and found that it was still able to block LTP and the formation of long term memories and the effects were similar for both the mice lacking PKMzeta and the control mice. Taken together, these results suggest that ZIP is not specific to PKMzeta and that PKMzeta is not involved in memory formation the way scientists thought. 

However, several questions remain… What is the ZIP acting on? What is PKMzeta doing if active all the time but not critical for memory formation? 


Volk et al. (2013). PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory. Nature493(7432):420-3. doi: 10.1038/nature11802

Lee et al. (2013). Prkcz null mice show normal learning and memory. Nature493(7432):416-9. doi: 10.1038/nature11803

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