PKMζ-PKCι/λ double-knockout demonstrates atypical PKC is crucial for the persistence of hippocampal LTP and spatial memory

Is long-term memory maintained by stable synaptic structures or persistent biochemical action? PKMζ, a persistently active atypical PKC (aPKC), is thought to be crucial for maintaining the late phase of long-term potentiation (late-LTP) and long-term memory through sustained kinase action. However, PKMζ-knockout mice express hippocampal LTP and spatial memory while lacking neocortical LTP, calling into question whether persistent kinases and PKMζ are fundamental to LTP and memory. In Tsokas et al., 2016, we showed PKCι/λ, the other aPKC, is the most likely compensating PKC isoform in PKMζ-knockout mice. In wild-type mice, PKCι/λ is critical to the initial generation of early-LTP and short-term memory, and PKMζ compensates for genetic deletion of PKCι/λ by supporting both early- and late-phase processes. Here, we found PKCι/λ persists in LTP and long-term memory when PKMζ is genetically deleted. We tested whether PKCι/λ functionally compensates for the loss of PKMζ by genetically ablating both aPKCs. Whereas deleting PKMζ and PKCι/λ individually induces compensation, deleting both aPKCs abolishes hippocampal late-LTP. Hippocampal ι/λ-ζ-double-knockout eliminates spatial long-term memory but not short-term memory. Thus, in the absence of PKMζ, a second persistent biochemical process compensates to maintain late-LTP and long-term memory.