Synaptic Tagging and Cross-Tagging: The Role of Protein Kinase Mζ in Maintaining Long-Term Potentiation But Not Long-Term Depression

Protein kinase Mζ (PKMζ) is a persistently active protein kinase C isoform that is synthesized during long-term potentiation (LTP) and is critical for maintaining LTP. According to “synaptic tagging,” newly synthesized, functionally important plasticity-related proteins (PRPs) may prolong potentiation not only at strongly tetanized pathways, but also at independent, weakly tetanized pathways if synaptic tags are set. We therefore investigated whether PKMζ is involved in tagging and contributes to a sustained potentiation by providing strong and weak tetanization to two independent pathways and then disrupting the function of the kinase by a selective myristoylated ζ-pseudosubstrate inhibitory peptide. We found that persistent PKMζ activity maintains potentiated responses, not only of the strongly tetanized pathway, but also of the weakly tetanized pathway. In contrast, an independent, nontetanized pathway was unaffected by the inhibitor, indicating that the function of PKMζ was specific to the tagged synapses. To further delineate the specificity of the function of PKMζ in synaptic tagging, we examined synaptic “cross-tagging,” in which late LTP in one input can transform early into late long-term depression (LTD) in a separate input or, alternatively, late LTD in one input can transform early into late LTP in a second input, provided that the tags of the weak inputs are set. Although the PKMζ inhibitor reversed late LTP, it did not prevent the persistent depression at the weakly stimulated, cross-tagged LTD input. Conversely, although the agent did not reverse late LTD, it blocked the persistent potentiation of weakly tetanized, cross-tagged synapses. Thus, PKMζ is the first LTP-specific PRP and is critical for the transformation of early into late LTP during both synaptic tagging and cross-tagging.