Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice

PKM zeta is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKM zeta in PKM zeta-null mice. Two hypotheses can account for these findings. First, PKM zeta is unimportant for LTP or memory. Second, PKM zeta is essential for late-LTP and long-term memory in wild-type mice, and PKM zeta-null mice recruit compensatory mechanisms. We find that whereas PKM zeta persistently increases in LTP maintenance in wild-type mice, PKC iota/lambda, a gene-product closely related to PKM zeta, persistently increases in LTP maintenance in PKM zeta-null mice. Using a pharmacogenetic approach, we find PKM zeta-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKM zeta-null mice without the target mRNA. Conversely, a PKC iota/lambda-antagonist disrupts late-LTP and spatial memory in PKM zeta-null mice but not in wild-type mice. Thus, whereas PKM zeta is essential for wild-type LTP and long-term memory, persistent PKC iota/lambda activation compensates for PKM zeta loss in PKM zeta-null mice.