PKM ζ-PKC ι / λ double-knockout demonstrates atypical PKC is crucial for the persistence of hippocampal LTP and spatial memory.

PKMζ, a persistently active atypical PKC (aPKC) isoform, is thought to maintain late-phase long-term potentiation (late-LTP) and long-term memory. However, PKMζ-knockout mice still exhibit hippocampal LTP and spatial memory while lacking neocortical LTP, questioning whether this kinase is fundamental to enduring synaptic potentiation and memory. Tsokas et al. (2016) showed the other aPKC, PKCι/λ, likely compensates for PKMζ during maintenance in the hippocampus of PKMζ-null mice. In wild-type mice, PKCι/λ drives early-LTP and short-term memory, while PKMζ compensates for PKCι/λ knockout by supporting both early- and late-phase processes. Here we show PKCι/λ persistently increases during maintenance in two mouse models: PKMζ-conditional knockout (cKO) mice, and double-knockout mice carrying both conditional deletion of PKCι/λ and constitutive loss of PKMζ. In the double-knockout mice, PKCι/λ was measured while the kinase was still present, prior to its inducible ablation, to characterize its compensatory upregulation in late-LTP before removal. To test whether this compensation was functional, we ablated PKCι/λ in the hippocampus of the double-knockout mice. The double-knockout eliminated late-LTP, whereas individual knockout of either aPKC alone showed normal-appearing LTP. Double-knockout also abolished spatial long-term memory without affecting short-term memory. Thus, when PKMζ is absent, PKCι/λ persists to maintain hippocampal late-LTP and long-term memory.