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The ζ-inhibitory peptide (ZIP) is considered a candidate inhibitor of the atypical protein kinase Mζ (PKMζ). ZIP has been shown to reverse established LTP and disrupt several forms of long-term memory. However, recent studies have challenged the specificity of ZIP, as it was reported to exert its effect also in PKMζ knock-out mice. These results raise the question of what are the targets of ZIP that may underlie its effect on LTP and memory. Here we report that ZIP as well as its inactive analog, scrambled ZIP, induced a dose-dependent increase in spontaneous activity of neurons in dissociated cultures of rat hippocampus. This was followed by a sustained elevation of intracellular calcium concentration ([Ca(2+)]i) which could not be blocked by conventional channel blockers. Furthermore, ZIP caused an increase in frequency of mEPSCs followed by an increase in membrane noise in patch-clamped neurons both in culture and in acute brain slices. Finally, at 5-10 μM, ZIP-induced excitotoxic death of the cultured neurons. Together, our results suggest that the potential contribution of cellular toxicity should be taken into account in interpretation of ZIP's effects on neuronal and behavioral plasticity. Significance statement: The ζ-inhibitory peptide (ZIP) is considered a candidate inhibitor of the atypical protein kinase Mζ (PKMζ). ZIP has been shown to reverse established LTP and disrupt several forms of long-term memory. Here we report that ZIP as well as its inactive analog, scrambled ZIP, induced a dose-dependent increase in spontaneous activity of neurons in dissociated cultures and brain slices of rat hippocampus. Furthermore, ZIP caused a dose- and time-dependent neuronal death in the dissociated cultures. These findings impact on the assumption that ZIP erases memory due to specific inhibition of PKMz.

Zeta Inhibitory Peptide, a Candidate Inhibitor of Protein Kinase M , Is Excitotoxic to Cultured Hippocampal Neurons