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

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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-ζ (PKM-ζ) has been reported to be necessary for both LTP maintenance and long-term memory2. Inhibiting PKM-ζ activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-ζ 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 PKM-ζ in LTP and memory relies heavily on pharmacological inhibition of PKM-ζ by ZIP. To further investigate the involvement of PKM-ζ in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-ζ and PKM-ζ. We find that both conventional and conditional PKC-ζ/PKM-ζ 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 PKC-ζ/PKM-ζ knockout mice, indicating that the effects of ZIP are independent of PKM-ζ.

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Figure 1: Normal LTP, gross brain morphology, and PKC isoform expression in conventional PKC-ζ/PKM-ζ KO mice.
Figure 2: LTP is intact in conditional PKC-ζ/PKM-ζ knockout mice.
Figure 3: ZIP is not specific for PKM-ζ.
Figure 4: Hippocampal-dependent learning and memory are intact in PKC-ζ/PKM-ζ KO mice.

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Acknowledgements

We thank G. Schütz for providing the CaMKII Cre-ERT2 mice, M. Gallagher and D. Smith for advice on behaviour and M. Coulter for technical support. We also thank all members of the Huganir lab for discussion and support. This work was supported by grants from the National Institute of Health (NS36715) and the Howard Hughes Medical Institute (to R.L.H.). L.J.V. is supported by a training grant from the National Institute of Health (T32MH15330).

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L.J.V., J.L.B. and R.L.H. designed experiments. L.J.V. and J.L.B performed experiments and analysed data. R.J. designed and generated the knockout animals. Y.Y. assisted in mating and genotyping mouse lines. L.J.V., J.L.B. and R.L.H. wrote the manuscript.

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Correspondence to Richard L. Huganir.

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Competing interests

Under a licensing agreement between Millipore Corporation and The Johns Hopkins University, R.L.H. is entitled to a share of royalties received by the University on sales of products described in this article. R.L.H. is a paid consultant to Millipore Corporation. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

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Volk, L., Bachman, J., Johnson, R. et al. PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature 493, 420–423 (2013). https://doi.org/10.1038/nature11802

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