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

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