ZIP: Drug that wipes memory

19 September 2017

Interview with

Todd Sacktor, State University of New York

How we store memory is still a hotly debated area. One researcher, in New York, believes that memories are stored in the connections - or synapses - which he likens to leaves touching between adjacent nerve cell “trees”; the strengths of those connections, he thinks, are controlled by a chemical called “PKM zeta”, which is made at each synapse when a memory is first laid down. And what Todd Sacktor and his colleagues have done is to create a drug called ZIP that disperses PKM Zeta and appears to wipe out memories. 

Todd - There are 86 billion nerve cells in the brain and one could picture each nerve cell as a tree that has a thousand leaves, and each is connected to another leaf of another tree - another nerve cell. When two leaves are touching, one leaf releases a chemical, which we call a neurotransmit, and then the adjacent leaf receiving that chemical starts to quiver and we call this connection a synapse. A memory is formed when the leaf that is responding to the release of the chemical responds twice as much as it normally would and that is due to a molecule called PKM Zeta. So when a memory is formed the PKM Zeta molecule gets synthesised as a memory is being formed; the PKM Zeta then resides in that leaf in the synapse.

Chris - Is it fair to summarise then and say I learned something and I make those leaves, which are connecting these trees fire off and because they’re touching they fire off, they form this association, this connection, strengthened by this enzyme PKM Zeta so that the way in which the information is stored is in the strength of those connections, and when I recall a memory it’s basically every tree that connected in my little forest is shaking to recall that memory? It’s created a sort of circuit which is the memory of my holiday in Paris or the apple pie I had for dinner?

Todd - If you recall the sight of an apple then part of that network is starting to fire and then it reverberates throughout the whole network and then the memory of having a particular dessert in Paris comes into your mind’s eye.

Chris - I can almost taste it now. Does that mean that it’s very difficult to unlearn something because once I’ve got those connections between my mental trees, how do I weaken it again if I then discover I was wrong and I shouldn’t have learned that, I should have learned something different?

Todd - Well, what’s thought is that when the group of trees are all firing at the same time that the synaptic connection, the PKM Zeta, breaks down briefly and then gets re-synthesised. So this is an opportunity at that time to change the memory, to add more information that was correct, or to get rid of information that was wrong - to update the memory.  It’s this re-synthesis of the PKM Zeta that we might be able to control with drugs to basically erase specific memories or to alter them.

Chris - Does this mean then that if you were to go into a part of the brain where a memory is stored and wipe away or break down the PKM Zeta which is there stabilising that memory, you could wipe a memory out?

Todd - This has been done in experimental animals. A drug called “zip” has been given to experimental animals and what we find is that all of the memories in that part of the brain are wiped out, even memories that are months old. But the drug doesn’t seem to harm the brain because even though the memories are gone, once the drug is washed out the animal could relearn and the learning is fine, and the storage of the memory is fine.

Chris - But you mentioned that when we do recall a memory or revisit a particular mental process that the PKM Zeta that’s there strengthening that circuit and holding that memory does, temporarily, breakdown and then reform. So might there be a way, rather than just wiping it all out just to prevent it reforming temporarily because that would mean you could discreetly wipe away the memories you were thinking about rather than every memory which could be pretty deleterious, couldn’t it, to wipe away everything?

Todd - That’s right. There’s ways to block specifically the synthesis of PKM Zeta and that should be a powerful way of erasing a specific memory. Basically having someone recall a memory and then give the drug that inhibits the synthesis, and that the PKM will get broken down specifically at the leaves that are connecting up that specific memory. But then, they won’t get re-synthesised again so the memory will be dampened or erased by only in those leaves in which the PKM Zeta had been degraded due to the activation, the quivering of those leaves.

Chris - What about elsewhere in the nervous system because the nervous system isn’t just the brain? We’ve got a spinal cord as well and people say that that does a lot of learning, particularly when you’re little to teach you to do motor things like walk around, but also pain. Is it possible that you could wipe out the pain memory and reprogramme the person’s spinal cord so something doesn’t hurt any more?

Todd - Yes. I think that’s actually where the clinical use of a compound such as zip would be because in experimental animals chronic neuropathic pain is like a memory in the pain pathways of the spinal cord and zip erases that.

Chris - Are there any other applications, not in the spinal cord, but higher up the nervous system where you could see erasing memories as being something clinically very beneficial and useful as a tool?

Todd - We don’t want to erase all of our memories, all associations in our brain or even in parts of the brain. What’s required, I think, is to develop the way to inhibit the action of PKM Zeta for specific memories. So the idea would be to recall the memory that’s painful or extremely debilitating, like in post traumatic stress disorder or depression. And then give a drug that will block the resynthesis of PKM Zeta and that should diminish or erase those specific maladaptive memories and keep the rest of our memories intact.

Comments

It is an interesting theory; however, these experiment have not been reproduced. Additionally, there are several high profile scientific publications that refute the PKMzeta theory.
Please, check the real science. Here are the references:
Memory molecule dethroned
http://www.nature.com/news/memory-molecule-dethroned-1.12139
PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory
https://www.nature.com/nature/journal/v493/n7432/full/nature11802.html
Prkcz null mice show normal learning and memory
https://www.nature.com/nature/journal/v493/n7432/full/nature11803.html

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