PKMζ-PKC{iota}/{lambda} double-knockout demonstrates atypical PKC is crucial for the persistence of hippocampal LTP and spatial memory

PKM{zeta}, a persistently active atypical PKC (aPKC) isoform, is thought to maintain the late phase of long-term potentiation (late-LTP) and long-term memory. PKM{zeta}-knockout mice, however, still show hippocampal LTP and spatial memory, while lacking neocortical LTP, calling into question whether the kinase is fundamental to enduring synaptic potentiation and memory. In Tsokas et al., 2016, we showed PKC{iota}/{lambda}, the other aPKC, is the most likely compensating PKC isoform in PKM{zeta}-null mice. In wild-type mice, PKC{iota}/{lambda} is critical to the initial generation of early-LTP and short-term memory, and PKM{zeta} compensates for the knockout of PKC{iota}/{lambda} by supporting both early- and late-phase processes. Here, we found PKC{iota}/{lambda} persistently increases in LTP and long-term memory in adult PKM{zeta}-conditional knockout (cKO) mice and in PKC{iota}/{lambda}-cKO-PKM{zeta}-null mice that express PKC{iota}/{lambda} prior to its genetic ablation, but not PKM{zeta}. We then tested whether PKC{iota}/{lambda} functionally compensates for the loss of PKM{zeta} by genetically eliminating PKC{iota}/{lambda} in the hippocampus of the PKC{iota}/{lambda}-cKO-PKM{zeta}-null mice. Whereas individual knockout of either PKM{zeta} or PKC{iota}/{lambda} results in compensatory LTP, double-knockout of both aPKCs eliminates late-LTP. Hippocampal {iota}/{lambda}-{zeta}-double-knockout abolishes spatial long-term memory but not short-term memory. Thus, in the absence of PKM{zeta}, the second aPKC, PKC{iota}/{lambda}, becomes persistently active to maintain late-LTP and long-term memory.