Neuroengineering memory: Something old, something new

Over the last week, it seems like everyone has sent me this NYT piece on PKM-zeta (about work in Todd Sacktor’s lab). I’m not sure why this work is being featured in the Times right now, since it’s a few years old. But it was news to me and I think it is of interest to anyone trying to understand structure-function relationships in the brain. In the original Science paper (from 2007), a pseudosubstrate inhibitor of PKM-zeta caused irreversible loss of a conditioned taste aversion memory (news and views here). I was unfamiliar with PKM-zeta, which appears to be a constitutively active form of PKC-zeta (a kinase that some might be more familiar with) and that lacks the autoinhibitory regulatory domain of PKC. The amazing phenomena is that, after treatment with ZIP (the pseudosubstrate that ties up PKM-zeta), the memory is permanently erased and doesn’t seem to return.

What’s going on? One tantalizing possibility is that the enzyme itself is directly related to the memory trace. This contradicts the (unproven) assumption of modern neuroscience that memories are stored solely in the synaptic strengths (ie. membrane-bound receptors) of a neuron. The other suggestion is that PKM-zeta is actively maintaining synapses and that enzymatic inhibition disrupts the precise maintenance of receptors or synaptic machinery. The effects happen quite fast (within 2 hours after drug injection), which seems short for receptor recycling but perhaps long enough for structural change to occur. I’m no expert on receptor movement: Is 2 hours long enough to add/remove a significant number of receptors?

Fascinating work but the method is blunt, wiping all experimentally-induced memories (and probably others too). Last month, another group reported (also in Science) selective erasure of a fear-conditioned memory using an interesting new genetic tool. Here, neurons in the amgydala that overexpressed CREB were found to be preferentially recruited into a fear memory trace (as shown in a previous Science paper). Incorporation into the memory trace was assayed by expression of the immediate-early gene (ie. activity-dependent) Arc. In the present study, they combine overexpression of CREB in a subset of neurons with cell death (via Diphtheria toxin in a transgenic mouse vulnerable to diphtheria). Apparently, normal mice lack the receptor (here a simian version is used) that confers pathogenicity for diphtheria. Thus, the viral construct both overexpresses CREB in a subset of neurons and selectively makes the same subset vulnerable to diphtheria. Ablation of just these neurons causes a permanent loss of the memory. Subsequent similar learning proceeds just fine (using the remaining neurons).

Can we say that the race is officially on to ablate just the synapses involved in the memory? I think so. Extra points if the ablation is reversible too!

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3 thoughts on “Neuroengineering memory: Something old, something new

  1. Neville, Just to let you know, the work that The Times mostly referred to was our 2006, not our 2007 Science article. PKMzeta works on glutamate receptor (AMPA receptor, GluR2 subunit) trafficking, a component of which cycles within minutes into and out of the synapse. PKMzeta acts to continually shift the distribution, doubling the number of postsynaptic receptors. The continual activity of the enzyme is required for maintaining the doubling and thus the memory. PKMzeta also maintains an increase in the size of spines, but this is not yet published.

    The CREB study shows that destruction of the specific neurons that were active during memory formation wipes out the memory retention. It does not address the mechanism of memory storage per se.

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  2. Todd, thanks for taking the time to read and respond to the post. And for the answer to my question about mechanisms! So, PKMzeta adds more AMPA receptors to maintain the memory? I assume this is synapse-specific, correct? (ie. not doubling AMPA at all synaptic sites but rather at specific sites) If you have any pointers to this literature about how PKMzeta works (at least to the degree it is currently known) and its effects on memory-specific synapses and spines, I’d love to read more on this. I myself am working on a project right now involving RNA editing of GluR2, so I’d like to learn more.

    You make a good point about the CREB study. Still, as a genetic tool, CREB overexpression is, currently, unique in allow us to control which neurons are part of a memory. For that alone, the study is fascinating, but it is hard not to speculate about pathways and mechanisms involved in memory storage. Thanks for the inspiring work and for contributing to the discussion here at Neurodudes!

    And folks, given what Todd mentioned about PKMzeta increasing the size of spines, I think this is the first time we’ve had “fresh science” featured on ND. And a hot topic at that! 🙂

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  3. Neville, PKMzeta actually works specifically on GluR2-dependent trafficking, as shown in Yao et al., PKM? maintains late-LTP by NSF/GluR2-dependent trafficking of postsynaptic AMPARs, J. Neurosci., 28:7820-7827 (2008). And yes, its effect is specific to the synapses undergoing LTP.

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