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

Peter Serrano,Stephen Maren,André A Fenton,John Hanna,Stephen M Taubenfeld,Jana Kenney,Jerry W Rudy,Cristina Alberini,Joshua M Zimmerman,Ann E Kelley,Eugenia L Friedman,Jerry C P Yin,Todd C Sacktor,Bai Lu

doi:10.1371/journal.pbio.0060318

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.

Highlights

The molecular mechanisms of initial memory consolidation have been extensively studied, little is known about the mechanism of persistent memory storage [1]
We showed that unpleasant memories are stored by the persistent action of an enzyme, a form of protein kinase C, termed protein kinase Mzeta (PKMf), because these memories can be rapidly erased by injecting a PKMf inhibitor into the brain
Are all forms of memory and information in the brain stored by PKMf? Here, we first confirmed with a second inhibitor of PKMf that unpleasant long-term memories in the hippocampus, a region of the brain critical for storing spatial information, are rapidly erased

Summary

Introduction

The molecular mechanisms of initial memory consolidation have been extensively studied, little is known about the mechanism of persistent memory storage [1]. The persistent phosphorylation by the autonomously active protein kinase C (PKC) isoform, protein kinase Mzeta (PKMf), has been shown to be critical for the maintenance of aversive long-term memories, place avoidance in the hippocampus [2] and conditioned taste aversion in the neocortex [3]. PKMf was initially identified as a persistently active kinase that is both necessary and sufficient for the maintenance of long-term potentiation (LTP) [4,5]. PKMf is a persistently active kinase because of its unique structure [4]. Most PKC isoforms consist of an N-terminal regulatory domain, which contains second messenger-binding sites and an autoinhibitory pseudosubstrate sequence, and a C-terminal catalytic.

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