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pT305-CaMKII stabilizes a learning-induced increase in AMPA receptors for ongoing memory consolidation after classical conditioning.

Naskar S, Wan H, Kemenes G - Nat Commun (2014)

Bottom Line: CaMKIINtide treatment significantly reduces the learning-induced elevation of both pT305-CaMKII and GluA1 levels and impairs associative long-term memory.Inhibition of proteasomal activity offsets the deleterious effects of CaMKIINtide on both GluA1 levels and long-term memory.These findings suggest that increased levels of pT305-CaMKII play a role in AMPAR-dependent memory consolidation by reducing proteasomal degradation of GluA1 receptor subunits.

View Article: PubMed Central - PubMed

Affiliation: 1] Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK [2].

ABSTRACT
The role of CaMKII in learning-induced activation and trafficking of AMPA receptors (AMPARs) is well established. However, the link between the phosphorylation state of CaMKII and the agonist-triggered proteasomal degradation of AMPARs during memory consolidation remains unknown. Here we describe a novel CaMKII-dependent mechanism by which a learning-induced increase in AMPAR levels is stabilized for consolidation of associative long-term memory. Six hours after classical conditioning the levels of both autophosphorylated pT305-CaMKII and GluA1 type AMPAR subunits are significantly elevated in the ganglia containing the learning circuits of the snail Lymnaea stagnalis. CaMKIINtide treatment significantly reduces the learning-induced elevation of both pT305-CaMKII and GluA1 levels and impairs associative long-term memory. Inhibition of proteasomal activity offsets the deleterious effects of CaMKIINtide on both GluA1 levels and long-term memory. These findings suggest that increased levels of pT305-CaMKII play a role in AMPAR-dependent memory consolidation by reducing proteasomal degradation of GluA1 receptor subunits.

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Proteasome inhibition offsets CaMKIINtide-induced memory impairment and the decrease in AMPARs(a) MG132 co-injected with CaMKIINtide at 6 h post-training rescues ALTM. Untreated paired (no injection, N=24), DMSO-injected (Vehicle, N=12), MG132-injected (N=12) and CaMKIINtide + MG132 injected (N=12) all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=24) and naïve (N=24) animals. Asterisks indicate significantly higher feeding responses to the CS compared with CaMKIINtide and naive levels. ANOVA: P<0.001. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05; CaMKIINtide-injected versus Naïve group, P>0.05; CaMKIINtide + MG132 injected group versus CaMKIINtide-injected and Naïve group, both P<0.05. (b) MG132 co-injected with CaMKIINtide at 6 h post-training rescues GluA1 receptor levels. Samples from untreated paired (no injection, N=4), DMSO-injected (Vehicle, N=8), MG132-injected (N=8) and CaMKIINtide + MG132 injected (N=8) animals all showed significantly higher GluA1 levels compared to CaMKIINtide-injected (N=8) and naïve (N=8) animals. Full-length blot is shown in Supplementary Fig. 8. Asterisks indicate significantly higher relative integrated density values compared with CaMKIINtide and naive baseline levels, respectively. One-way ANOVA: P<0.006. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05. One-sample t-tests: CaMKIINtide-injected versus naïve baseline, P>0.05; all other groups versus naïve baseline, P<0.05. These experiments were replicated twice. All data are presented as means±SEM.
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Figure 9: Proteasome inhibition offsets CaMKIINtide-induced memory impairment and the decrease in AMPARs(a) MG132 co-injected with CaMKIINtide at 6 h post-training rescues ALTM. Untreated paired (no injection, N=24), DMSO-injected (Vehicle, N=12), MG132-injected (N=12) and CaMKIINtide + MG132 injected (N=12) all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=24) and naïve (N=24) animals. Asterisks indicate significantly higher feeding responses to the CS compared with CaMKIINtide and naive levels. ANOVA: P<0.001. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05; CaMKIINtide-injected versus Naïve group, P>0.05; CaMKIINtide + MG132 injected group versus CaMKIINtide-injected and Naïve group, both P<0.05. (b) MG132 co-injected with CaMKIINtide at 6 h post-training rescues GluA1 receptor levels. Samples from untreated paired (no injection, N=4), DMSO-injected (Vehicle, N=8), MG132-injected (N=8) and CaMKIINtide + MG132 injected (N=8) animals all showed significantly higher GluA1 levels compared to CaMKIINtide-injected (N=8) and naïve (N=8) animals. Full-length blot is shown in Supplementary Fig. 8. Asterisks indicate significantly higher relative integrated density values compared with CaMKIINtide and naive baseline levels, respectively. One-way ANOVA: P<0.006. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05. One-sample t-tests: CaMKIINtide-injected versus naïve baseline, P>0.05; all other groups versus naïve baseline, P<0.05. These experiments were replicated twice. All data are presented as means±SEM.

Mentions: In this experiment we used 5 groups of classically conditioned and one group of naïve animals. Six hours after classical conditioning, the first group of trained animals was left untreated, the second group was injected with vehicle, the third group was injected with MG132, the fourth group was injected with CaMKIINtide, while the fifth trained group was injected with a mixture of CaMKIINtide and MG132. When the trained animals were tested with the CS 24 h after conditioning (and 18 h after injection when drugs or vehicle was administered) and also compared against a naïve control group, an ANOVA indicated a source of significant difference among the 6 groups (Fig. 9a). Post-hoc tests showed that the CaMKIINtide injected group gave a significantly weaker feeding response to the CS than any of the other trained groups with the response only being marginally higher than the CS response in the naïve control group. The most important finding of this experiment however was that when CaMKIINtide was injected together with MG132, memory impairment did not occur at 24 h after training, confirming that proteasomal inhibition can rescue memory from the impairment caused by inhibition of CaMKII autophosphorylation at T305. Interestingly, treatment with MG132 alone seemed to have a mild boosting effect on memory 18 h later, although this was not significant.


pT305-CaMKII stabilizes a learning-induced increase in AMPA receptors for ongoing memory consolidation after classical conditioning.

Naskar S, Wan H, Kemenes G - Nat Commun (2014)

Proteasome inhibition offsets CaMKIINtide-induced memory impairment and the decrease in AMPARs(a) MG132 co-injected with CaMKIINtide at 6 h post-training rescues ALTM. Untreated paired (no injection, N=24), DMSO-injected (Vehicle, N=12), MG132-injected (N=12) and CaMKIINtide + MG132 injected (N=12) all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=24) and naïve (N=24) animals. Asterisks indicate significantly higher feeding responses to the CS compared with CaMKIINtide and naive levels. ANOVA: P<0.001. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05; CaMKIINtide-injected versus Naïve group, P>0.05; CaMKIINtide + MG132 injected group versus CaMKIINtide-injected and Naïve group, both P<0.05. (b) MG132 co-injected with CaMKIINtide at 6 h post-training rescues GluA1 receptor levels. Samples from untreated paired (no injection, N=4), DMSO-injected (Vehicle, N=8), MG132-injected (N=8) and CaMKIINtide + MG132 injected (N=8) animals all showed significantly higher GluA1 levels compared to CaMKIINtide-injected (N=8) and naïve (N=8) animals. Full-length blot is shown in Supplementary Fig. 8. Asterisks indicate significantly higher relative integrated density values compared with CaMKIINtide and naive baseline levels, respectively. One-way ANOVA: P<0.006. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05. One-sample t-tests: CaMKIINtide-injected versus naïve baseline, P>0.05; all other groups versus naïve baseline, P<0.05. These experiments were replicated twice. All data are presented as means±SEM.
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Figure 9: Proteasome inhibition offsets CaMKIINtide-induced memory impairment and the decrease in AMPARs(a) MG132 co-injected with CaMKIINtide at 6 h post-training rescues ALTM. Untreated paired (no injection, N=24), DMSO-injected (Vehicle, N=12), MG132-injected (N=12) and CaMKIINtide + MG132 injected (N=12) all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=24) and naïve (N=24) animals. Asterisks indicate significantly higher feeding responses to the CS compared with CaMKIINtide and naive levels. ANOVA: P<0.001. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05; CaMKIINtide-injected versus Naïve group, P>0.05; CaMKIINtide + MG132 injected group versus CaMKIINtide-injected and Naïve group, both P<0.05. (b) MG132 co-injected with CaMKIINtide at 6 h post-training rescues GluA1 receptor levels. Samples from untreated paired (no injection, N=4), DMSO-injected (Vehicle, N=8), MG132-injected (N=8) and CaMKIINtide + MG132 injected (N=8) animals all showed significantly higher GluA1 levels compared to CaMKIINtide-injected (N=8) and naïve (N=8) animals. Full-length blot is shown in Supplementary Fig. 8. Asterisks indicate significantly higher relative integrated density values compared with CaMKIINtide and naive baseline levels, respectively. One-way ANOVA: P<0.006. Tukey’s: CaMKIINtide-injected versus all other trained groups, P<0.05. One-sample t-tests: CaMKIINtide-injected versus naïve baseline, P>0.05; all other groups versus naïve baseline, P<0.05. These experiments were replicated twice. All data are presented as means±SEM.
Mentions: In this experiment we used 5 groups of classically conditioned and one group of naïve animals. Six hours after classical conditioning, the first group of trained animals was left untreated, the second group was injected with vehicle, the third group was injected with MG132, the fourth group was injected with CaMKIINtide, while the fifth trained group was injected with a mixture of CaMKIINtide and MG132. When the trained animals were tested with the CS 24 h after conditioning (and 18 h after injection when drugs or vehicle was administered) and also compared against a naïve control group, an ANOVA indicated a source of significant difference among the 6 groups (Fig. 9a). Post-hoc tests showed that the CaMKIINtide injected group gave a significantly weaker feeding response to the CS than any of the other trained groups with the response only being marginally higher than the CS response in the naïve control group. The most important finding of this experiment however was that when CaMKIINtide was injected together with MG132, memory impairment did not occur at 24 h after training, confirming that proteasomal inhibition can rescue memory from the impairment caused by inhibition of CaMKII autophosphorylation at T305. Interestingly, treatment with MG132 alone seemed to have a mild boosting effect on memory 18 h later, although this was not significant.

Bottom Line: CaMKIINtide treatment significantly reduces the learning-induced elevation of both pT305-CaMKII and GluA1 levels and impairs associative long-term memory.Inhibition of proteasomal activity offsets the deleterious effects of CaMKIINtide on both GluA1 levels and long-term memory.These findings suggest that increased levels of pT305-CaMKII play a role in AMPAR-dependent memory consolidation by reducing proteasomal degradation of GluA1 receptor subunits.

View Article: PubMed Central - PubMed

Affiliation: 1] Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK [2].

ABSTRACT
The role of CaMKII in learning-induced activation and trafficking of AMPA receptors (AMPARs) is well established. However, the link between the phosphorylation state of CaMKII and the agonist-triggered proteasomal degradation of AMPARs during memory consolidation remains unknown. Here we describe a novel CaMKII-dependent mechanism by which a learning-induced increase in AMPAR levels is stabilized for consolidation of associative long-term memory. Six hours after classical conditioning the levels of both autophosphorylated pT305-CaMKII and GluA1 type AMPAR subunits are significantly elevated in the ganglia containing the learning circuits of the snail Lymnaea stagnalis. CaMKIINtide treatment significantly reduces the learning-induced elevation of both pT305-CaMKII and GluA1 levels and impairs associative long-term memory. Inhibition of proteasomal activity offsets the deleterious effects of CaMKIINtide on both GluA1 levels and long-term memory. These findings suggest that increased levels of pT305-CaMKII play a role in AMPAR-dependent memory consolidation by reducing proteasomal degradation of GluA1 receptor subunits.

Show MeSH
Related in: MedlinePlus