ZIP – the cure for the ‘Embarrassing Kid’

For the latest van der Graaf Generator album (A Grounding in Numbers), Peter Hammill penned a song called ‘Embarrassing Kid’ wherein he lamented the fact that he could not escape the mistakes of his younger, and more foolish, self. Well… now… he can, sort of…

In the 9th May edition of the podcast series, ‘Are we Alone?’ , titled ‘Thanks for the memories’ the hosts interviewed Tod Sacktor, whose research group has developed ZIP. ZIP stands for Zeta Inhibitory Peptide. Sacktor and his group had a theory about the role of the PKM-zeta enzyme in the formation of long-term memories. They tested this through a simple experiment: They trained some rats by putting them in a maze and every time they entered a certain space the rats received a small, unpleasant electric shock. The rats learnt to consistently avoid that room. If Sacktor’s theory was correct then injecting the rats with ZIP would inhibit the effect of PMK-zeta, disturb the recall of long-term memory and cause the rats to forget about the shock so they should start entering the room again. That’s exactly what happened and the effect lasted a long time.

I’m not sure what is more troubling about this. Is it (a) the potential applications of such a chemical or (b) the fact that it provides further indications that our memories (in all their richness) are fundamentally chemical!

Other nuggets from the same show:
(1) Forgetting is an essential process for a healthy mind. We need to forget to sieve through the mass of data that is everyday life in order to hold on to what is meaningful.
(2) There is no central bit of the brain that does ‘memory’ instead it is distributed across the brain. This tallies with so much about brain functioning but it does move into the foreground the question of ‘what are the mechanisms of association between different fragments of the same memory and of association between different memories?’

That was 2011… In 2013, 2 papers were published in Nature (Vol. 293, 17 January 2013) which challenged, and made more complex, the relationship between memory, PKM-zeta and ZIP. (I’m a lot behind in my reading of Nature articles, so I’ve only just got round to reading these!)

Anyway, to clarify, the papers (and, it seems, much of the research in this area) consider Long Term Potentiation (LTP) which is a form of long-term synaptic strengthening and use this as a cellular proxy for memory. The idea being that as new memories are formed then the connections between relevant neurons will be strengthened over the long-term either by the strengthening of existing synapses or the formation of new ones.

What the authors in both papers did, which is both ingenious and (to me) astounding is genetically engineer mice without the PKM-zeta gene. There are differences between the methodologies in the 2 groups which I’m not going to go into. 2 findings emerged from the papers:

(1) The mice without the PKM-zeta enzyme still demonstrated normal learning and memory. This unsettles the idea that PKM-zeta has a central role in LTP and leaves us with a more complex picture. As the author of the review wrote, “Hundreds of molecules are probably involved in the formation and maintenance of memory, and within this ‘mnemome’ there may be a fair degree of redundancy and degeneracy – whereby related molecules compensate for each others’ deficiency. […] So asking whether PKM-zeta could really be ‘the’ memory molecule is probably not the right question, as it fails to capture the complexity of the interactions between the molecules within the mnemome. Given evolution’s penchant for redundancy, it seems unlikely that any single molecule will play this part solo. Rather, the question should be one of degree – is a molecule a lead player (and therefore irreplaceable) or does it have more of a supporting role? The casting debate on PKM-zeta will, no doubt, continue.”
(2) Even in the mice without the PKM-zeta enzyme, ZIP still disrupts both established LTP and memory! There is no question that ZIP is affective, it has been shown to “disrupt established spatial, fear, appetitive, habit and sensorimotor memories in rodents and sensitization memory in the sea slug Aplysia” but now the mechanism whereby it achieves these effects has been thrown into question.

From Nature, 493, 17 January 2013
Frankland, P.W. & Josselyn, S.A., ‘Memory and the single molecule’, p312-313
This is a good review of the 2 papers. The papers themselves are:
Lee., A.M., et al., ‘Prkcz null mice show normal learning and memory’, p416-419
Volk, L.J., et al., ‘PKM-zeta is not required for hipocampal synaptic plasticity, learning and memory’, p420-423

In truth, the papers do not change the fundamental picture about the molecular roots of memory. What I remain unclear about is the way that elements of complex memories (such as, say, my memory of a pet dog) are co-ordinated and combined on a molecular level.

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About Bruce Davenport

Museum educator and researcher.
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