Abstract
Protein kinase M-ζ (PKM-ζ) is a constitutively active form of atypical protein kinase C that is exclusively expressed in the brain and implicated in the maintenance of long-term memory1,2,3,4,5,6,7,8,9. Most studies that support a role for PKM-ζ in memory maintenance have used pharmacological PKM-ζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here we use a genetic approach and target exon 9 of the Prkcz gene to generate mice that lack both protein kinase C-ζ (PKC-ζ) and PKM-ζ (Prkcz−/− mice). Prkcz−/− mice showed normal behaviour in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behaviour. Notably, Prkcz−/− mice did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens reduced expression of cocaine-conditioned place preference in Prkcz−/− mice. In vitro, ZIP and scrambled ZIP inhibited PKM-ζ, PKC-ι and PKC-ζ with similar inhibition constant (Ki) values. Chelerythrine was a weak inhibitor of PKM-ζ (Ki = 76 μM). Our findings show that absence of PKM-ζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKM-ζ is not present.
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Acknowledgements
We thank V. N. Kharazia and A. J. Lean for assistance. This work was supported by National Institutes of Health grant AA017072 (R.O.M.), a Canadian Institute of Health Research Post-doctoral Fellowship (A.M.L.), and funds provided by the State of California for medical research on alcohol and drug abuse to UCSF.
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A.M.L. designed experiments, collected and analysed data, and wrote the manuscript. B.R.K., J.P.L., M.E.Z., C.Q., T.M. and S.C.F.-W. collected and analysed data. D.W. collected and analysed the data from the in vitro kinase assays. J.D. produced the constructs for the kinase assays and for generation of the mutant mice, and genotyped the mice. R.O.M. designed experiments, analysed data and co-authored the manuscript.
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Lee, A., Kanter, B., Wang, D. et al. Prkcz null mice show normal learning and memory. Nature 493, 416–419 (2013). https://doi.org/10.1038/nature11803
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DOI: https://doi.org/10.1038/nature11803
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