PKMζ Maintains Spatial, Instrumental, and Classically Conditioned Long-Term Memories

How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKM zeta ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKM zeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKM zeta activity. We then examined, using ZIP, the effect of PKM zeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKM zeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKM zeta activity. Similarly, PKM zeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKM zeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKM zeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKM zeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information. Author Summary How long-term memories are stored as physical traces in the brain is a fundamental question in neuroscience. Recently, we discovered the first molecular mechanism of long-term memory storage. We showed that unpleasant memories are stored by the persistent action of an enzyme, a form of protein kinase C, termed PKM zeta , because these memories can be rapidly erased by injecting a PKM zeta inhibitor into the brain. But are all forms of memory and informatio