PKMζ maintains memories by regulating GluR2-dependent AMPA receptor trafficking

Abstract

The maintenance of long-term memory in hippocampus, neocortex and amygdala requires the persistent action of the atypical protein kinase C isoform, protein kinase Mzeta (PKMzeta). We found that inactivating PKMzeta in the amygdala impaired fear memory in rats and that the extent of the impairment was positively correlated with a decrease in postsynaptic GluR2. Blocking the GluR2-dependent removal of postsynaptic AMPA receptors abolished the behavioral impairment caused by PKMzeta inhibition and the associated decrease in postsynaptic GluR2 expression, which correlated with performance. Similarly, blocking this pathway for removal of GluR2-containing receptors from postsynaptic sites in amygdala slices prevented the reversal of long-term potentiation caused by inactivating PKMzeta. Similar behavioral results were obtained in the hippocampus for unreinforced recognition memory of object location. Together, these findings indicate that PKMzeta maintains long-term memory by regulating the trafficking of GluR2-containing AMPA receptors, the postsynaptic expression of which directly predicts memory retention.

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 .…”

“…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.…”

Cellular and subcellular localization of PKMζ

“…Quantification of the subcellular distribution of PKMz in spines after LTP and memory formation will be an important area for future investigation. Our current results are consistent with the recent quantitative electron microscopic analysis in dentate gyrus of rhesus monkeys by Hara and co-workers [38], who used an antibody recognizing atypical PKC (both z and i/l isoforms), as well as a second antibody recognizing AMPA receptor subunit GluA2, whose postsynaptic trafficking is regulated by PKMz [32,39,40]. They found that higher proportions of dendritic spines coexpressing these two molecules correlated with faster delayed non-matching-to-sample-task acquisition and more accurate recognition memory [38].…”

“…They found that higher proportions of dendritic spines coexpressing these two molecules correlated with faster delayed non-matching-to-sample-task acquisition and more accurate recognition memory [38]. Their findings are compatible with the synaptic localization of PKMz demonstrated here and PKMz's role in GluA2-mediated AMPA receptor trafficking [32,39,40].…”

“…Within spines containing the kinase, PKMz is found in multiple locations-within the PSD, adjacent to the PSD and in clusters at the centre of the spine. This variation in intraspine location is consistent with PKMz's proposed mechanism of synaptic potentiation by altering the dynamics of AMPA receptor trafficking into and out of the PSD through the regulation of receptor endocytosis [2,32]. Initial work with mouse knock-outs of PKMz have questioned the role of PKMz in synaptic plasticity and memory [33,34], reporting normal LTP and long-term memory in the constitutive PKMz knock-out for various tasks.…”