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

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.

Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear

“…Although previous studies have reported a synaptic insertion of AMPARs at hippocampal and amygdaloid synapses 24 h after auditory fear conditioning 19,42 , there appears to be no increase in dorsohippocampal AMPAR surface expression 1 day after contextual foreground conditioning (without tone) as measured here. This is in line with previous research that showed that disruption of GluA2 surface expression in the hippocampus 1 day after conditioning has no effect on maintenance of contextual fear memory 43,44 , in contrast to the amygdala 43 .…”

“…This is in line with previous research that showed that disruption of GluA2 surface expression in the hippocampus 1 day after conditioning has no effect on maintenance of contextual fear memory 43,44 , in contrast to the amygdala 43 .…”

“…Although previous studies have reported a synaptic insertion of AMPARs at hippocampal and amygdaloid synapses 24 h after auditory fear conditioning 19,42 , there appears to be no increase in dorsohippocampal AMPAR surface expression 1 day after contextual foreground conditioning (without tone) as measured here. This is in line with previous research that showed that disruption of GluA2 surface expression in the hippocampus 1 day after conditioning has no effect on maintenance of contextual fear memory 43,44 , in contrast to the amygdala 43 .Reconsolidation has mostly been studied as the phenomenon that creates memory amnesia, due to the well-known effect of agents to block the further expression of memory [3][4][5][6][7][8] . However, recent data indicates that reconsolidation is also adaptive in nature and has two main roles.…”

The roles of protein kinases in learning and memory

“…First, it was shown that injection of ZIP into the hippocampus erases a consolidated spatial LTM (Pastalkova et al 2006). Further, ZIP injection into the basolateral amygdala blocks cued and contextual fear LTM as well as inhibitory avoidance LTM (Serrano et al 2008;Kwapis et al 2009). However, not all memory storage processes are ZIP-dependent (for review, see Glanzman 2013).…”

“…However, not all memory storage processes are ZIP-dependent (for review, see Glanzman 2013). For example, injection of ZIP into the dorsal hippocampus does not affect contextual fear LTM, although this part of the hippocampus is required for contextual LTM (Serrano et al 2008;Kwapis et al 2009). A recent study has claimed that ZIP does not block specifically PKMz .…”