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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 1 h before but not 1 h after CaMKIINtide treatment offsets memory impairment(a) MG132 injected 1 h before treatment with CaMKIINtide at 6 h post-training offsets the effect of CaMKIINtide on LTM. Untreated paired (no injection, N=22), DMSO-injected (Vehicle, N=14), and MG132->CaMKIINtide injected (N=15) groups of animals all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23) and naïve (N=22) animals. (b) MG132 injected 1 h after CaMKIINtide treatment at 6 h post-training does not offset the effect of CaMKIINtide on LTM. The untreated paired (no injection, N=22) and DMSO-injected (Vehicle, N=13) groups of animals showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23), CaMKIINtide −> MG132 injected and naïve (N=23) animals. Asterisks indicate significantly higher feeding responses to the CS compared against CaMKIINtide and naïve levels in (a) and CaMKIINtide, CaMKIINtide->MG132 and naïve levels in (b) (ANOVAs, P<0.001; Tukey’s, P<0.05). These experiments were replicated twice. All data are presented as means±SEM.
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Figure 10: Proteasome inhibition 1 h before but not 1 h after CaMKIINtide treatment offsets memory impairment(a) MG132 injected 1 h before treatment with CaMKIINtide at 6 h post-training offsets the effect of CaMKIINtide on LTM. Untreated paired (no injection, N=22), DMSO-injected (Vehicle, N=14), and MG132->CaMKIINtide injected (N=15) groups of animals all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23) and naïve (N=22) animals. (b) MG132 injected 1 h after CaMKIINtide treatment at 6 h post-training does not offset the effect of CaMKIINtide on LTM. The untreated paired (no injection, N=22) and DMSO-injected (Vehicle, N=13) groups of animals showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23), CaMKIINtide −> MG132 injected and naïve (N=23) animals. Asterisks indicate significantly higher feeding responses to the CS compared against CaMKIINtide and naïve levels in (a) and CaMKIINtide, CaMKIINtide->MG132 and naïve levels in (b) (ANOVAs, P<0.001; Tukey’s, P<0.05). These experiments were replicated twice. All data are presented as means±SEM.

Mentions: To investigate the time windows in which the administration of MG132 can rescue the 24 h memory from CaMKIINtide-induced impairment, we performed two further experiments. In one experiment administration of MG132 preceded that of CaMKIINtide by 1 h and in another experiment it followed the administration of CaMKIINtide by 1 h. These experiments showed that injection with MG132 at 5 h had a similar memory rescuing effect on trained animals treated with CaMKIINtide at 6 h post-training (Fig. 10a) as when the two drugs were co-injected at 6 h post-training. However, when MG132 was administered with a 1 h delay after CaMKIINtide treatment at 6 h it was no longer effective in rescuing long-term memory (Fig. 10b).


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 1 h before but not 1 h after CaMKIINtide treatment offsets memory impairment(a) MG132 injected 1 h before treatment with CaMKIINtide at 6 h post-training offsets the effect of CaMKIINtide on LTM. Untreated paired (no injection, N=22), DMSO-injected (Vehicle, N=14), and MG132->CaMKIINtide injected (N=15) groups of animals all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23) and naïve (N=22) animals. (b) MG132 injected 1 h after CaMKIINtide treatment at 6 h post-training does not offset the effect of CaMKIINtide on LTM. The untreated paired (no injection, N=22) and DMSO-injected (Vehicle, N=13) groups of animals showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23), CaMKIINtide −> MG132 injected and naïve (N=23) animals. Asterisks indicate significantly higher feeding responses to the CS compared against CaMKIINtide and naïve levels in (a) and CaMKIINtide, CaMKIINtide->MG132 and naïve levels in (b) (ANOVAs, P<0.001; Tukey’s, P<0.05). These experiments were replicated twice. All data are presented as means±SEM.
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Figure 10: Proteasome inhibition 1 h before but not 1 h after CaMKIINtide treatment offsets memory impairment(a) MG132 injected 1 h before treatment with CaMKIINtide at 6 h post-training offsets the effect of CaMKIINtide on LTM. Untreated paired (no injection, N=22), DMSO-injected (Vehicle, N=14), and MG132->CaMKIINtide injected (N=15) groups of animals all showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23) and naïve (N=22) animals. (b) MG132 injected 1 h after CaMKIINtide treatment at 6 h post-training does not offset the effect of CaMKIINtide on LTM. The untreated paired (no injection, N=22) and DMSO-injected (Vehicle, N=13) groups of animals showed significantly higher feeding responses to the CS compared to CaMKIINtide-injected (N=23), CaMKIINtide −> MG132 injected and naïve (N=23) animals. Asterisks indicate significantly higher feeding responses to the CS compared against CaMKIINtide and naïve levels in (a) and CaMKIINtide, CaMKIINtide->MG132 and naïve levels in (b) (ANOVAs, P<0.001; Tukey’s, P<0.05). These experiments were replicated twice. All data are presented as means±SEM.
Mentions: To investigate the time windows in which the administration of MG132 can rescue the 24 h memory from CaMKIINtide-induced impairment, we performed two further experiments. In one experiment administration of MG132 preceded that of CaMKIINtide by 1 h and in another experiment it followed the administration of CaMKIINtide by 1 h. These experiments showed that injection with MG132 at 5 h had a similar memory rescuing effect on trained animals treated with CaMKIINtide at 6 h post-training (Fig. 10a) as when the two drugs were co-injected at 6 h post-training. However, when MG132 was administered with a 1 h delay after CaMKIINtide treatment at 6 h it was no longer effective in rescuing long-term memory (Fig. 10b).

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