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

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Abstract
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 (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ 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 PKMζ activity. We then examined, using ZIP, the effect of PKMζ 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, PKMζ 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 PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ 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. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ 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. 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 PKMζ, because these memories can be rapidly erased by injecting a PKMζ inhibitor into the brain. But are all forms of memory and information in the brain stored by PKMζ? Here, we first confirmed with a second inhibitor of PKMζ that unpleasant long-term memories in the hippocampus, a region of the brain critical for storing spatial information, are rapidly erased. We then examined other memories stored in the hippocampus and the basolateral amygdala, another region critical for emotional memories. We tested memories for specific places, both unpleasant and rewarding, memories for general background information, associations between a sound and a fearful event, like that studied by Pavlov, and memories for performing a specific action. We found that PKMζ stores specific associations, both unpleasant and rewarding, for places, events, and actions, and is thus a general mechanism for memory storage in the brain.