Huganir Volk Nature Knockout PKMζ PKM-zeta not required for hippocampal memory

PKM-ζ aka PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory

Lenora J. Volk, Julia L. Bachman, Richard Johnson, Yilin Yu, and Richard L. Huganir

Nature 2013


Here’s the abstract:

Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time1, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-zeta (PKM-zeta) has been reported to be necessary for both LTP maintenance and long-term memory2. Inhibiting PKM-zeta activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-zeta pseudosubstrate sequence reverses established LTP in vitro and in vivo3,4. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance4, conditioned taste aversion5, fear conditioning and spatial learning6. However, most of the evidence supporting a role for PKMz in LTP and memory relies heavily on pharmacological inhibition of PKMz by ZIP. To further investigate the involvement of PKMz in the maintenance of LTP and memory, we generated transgenic mice lacking PKCz and PKMz. We find that both conventional and conditional PKCz/ PKMz knockout mice show normal synaptic transmission and LTP at Schaffer collateral–CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKCz/PKMz knockout mice, indicating that the effects of ZIP are independent of PKMz.

See the paper on the Nature website

I’ve just submitted a paper to Nature Neuro showing that ZIP administered ICV disrupts drug memory maintenance, so I’m going to remain neutral on this. However, if there’s anyone out there that has an opinion (Todd Sacktor?) I’d love to hear it. I’m sure others would as well. I thought we had a pretty fruitful discussion last time.

5 thoughts on “Huganir Volk Nature Knockout PKMζ PKM-zeta not required for hippocampal memory

  1. Hi Frank, I also think that LTM is encoded through scaffold associated proteins. Could you please elaborate on your ideas?

  2. Hi, Bradley. Thank you so much for giving me the opportunity to present my ideas here. I just published the detail on my website: In a nutshell, I do not think LTM is stored in spines because of protein turnover and a constitutively active CaMKII inhibitor, CaMKIIN, which are constantly erasing memory traces in spines. Since plasticity-related proteins (PRPs, such as CaMKII and PSD-95) in spines must ultimately come from the soma via microtubule transport, I think LTM could be encoded in microtubule tracks. Whether a spine is active or not depends on whether or not PRPs can be delivered to the spine via a specific microtubule track.

    Instead of PKCζ and PKMζ, two other protein kinase C isoforms, α and ε, have been shown to play a central role in LTM. Hence, during memory consolidation, the communication between the hippocampus and neocortex eventually leads to these PKC activation. The detailed mechanism is explained on my website. Here I would like to point out that PKC activators are being developed as therapeutics for Alzheimer’s disease. This approach seems quite promising. If LTM is indeed encoded in microtubule tracks, then memories could be restored by PKC activators (which stimulate synthesis of PRPs) as long as the microtubule tracks are intact, even after spines have been destroyed!

  3. This is a very interesting hypothesis Frank, and I agree that microtubules must play a big role in directing the transport of RNA and proteins to potentiated synapses. However, here’s something to consider: microtubules bring material to all synapses, not just potentiated synapses. Current theories suggest that microtubules deliver dormant PRPs (in the form of untranslated RNA or inhibited protein) to synapses, and then when there is a local increase of activity at a synapse, these dormant PRPs can quickly be turned on. For you to advance your hypothesis, you’ll need to show that microtubules can alter the type of cargo they carry to a potentiated vs non-potentiated synapse.

    P.S. I’d be willing to exchange a link from my website for a link from your website.

  4. Bradley, thanks for your comments. I have updated the article, Long-Term Memory: PKC and Microtubule Tracks, to clarify these points.

    According to the Microtubule Track (MTT) hypothesis, the synaptic potentiation is determined by three major factors: MTTs, PSD-95 expression and CaMKII activity. The long-term memory is encoded in MTTs, while the short-term fluctuation of the synaptic potentiation is shaped by PSD-95 expression and CaMKII activity.

    Most PRPs and their mRNAs do not need specific MTTs for their delivery to any particular spines. PSD-95 is probably the only one which requires targeted transport, because it can recruit other PRPs to the synapse. Once a specific MTT for the delivery of PSD-95 to a synapse has been established, the synaptic potentiation can be modulated by PSD-95 expression. The more PSD-95 are synthesized in the soma, the more they will be delivered to the target synapse, where they can retain AMPAR at the synapse, thereby enhancing the synapse. The PKC activator, Bryostatin, has been shown to stimulate PSD-95 expression and induces synaptogenesis.

    The memory traces maintained by CaMKII are short lived, due to the constitutively active CaMKII inhibitor, CaMKIIN. Prof. Chiara Cirelli mentioned to me that CaMKIIN is significantly up-regulated during sleep. Hence, a substantial fraction of memory traces in the spines will be erased during sleep. The memories without being encoded in MTTs will be lost forever, but those encoded in MTTs can still be recalled, depending on CaMKII activity and PSD-95 expression.

    In short, the potentiation at spines affects how easy an event can be recalled, whereas the MTTs for PSD-95 dictate the existence of the memory.

    P.S. It is a good idea for my visitors to join the discussion. I have added a link from my website to this page .

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