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
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.
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.