PKMζ-PKCι/λ double-knockout reveals the atypical PKCs are crucial for hippocampal late-LTP and spatial long-term memory

PKMζ, a persistently active, atypical PKC (aPKC) isoform, maintains enduring long-term potentiation (LTP) and memory in wild-type (WT) mice; however, hippocampal LTP and memory in PKMζ-knockout (ζ-KO) mice are maintained by compensation. Although ζ-KO eliminates neocortical LTP, hippocampal LTP may be sustained by another aPKC, ι/λ (PKCι). PKCι is critical for the generation of an early phase of LTP and short-term memory, and its genetic deletion is compensated by PKMζ. Using a double knockout strategy, deleting both PKCι and PKMζ (ι/ζ-dKO) in hippocampus, we report that ι/ζ-dKO eliminates enduring LTP and spatial long-term memory but shows an early-phase, short-lasting LTP and short-term memory. ZIP, an inhibitor of both PKMζ and PKCι that disrupts LTP in WT and PKMζ-null hippocampus, does not affect LTP in ι/ζ-dKO hippocampus, suggesting ZIP disrupts LTP by targeting PKMζ or PKCι. Thus, the double-KO reveals that additional compensatory short-term processes can be induced without aPKCs, whereas additional long-term processes cannot. We conclude that PKMζ, under normal conditions, and PKCι as an essential back-up are crucial for the persistence of hippocampal LTP and spatial memory.