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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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T305 autophosphorylation of CaMKII regulates AMPAR protein levels in the ‘learning ganglia’Example GluA1 western blot bands from a paired and CaMKIINtide-treated, a paired and vehicle-treated and a naïve sample, run on the same gel, are shown above the graphs (full-length blot in Supplementary Fig. 7f). Density data obtained from CaMKIINtide (N=8) and vehicle (N=8) samples were normalized to the mean of the density data obtained from naïve samples (N=8), which provided a baseline value of 1. The asterisk indicates significant difference compared to both the naïve baseline and the level measured after CaMKIINtide treatment. One-sample t-tests: CaMKIINtide versus naïve baseline, P=0.41 (n.s.); Vehicle versus baseline, P<0.05. Two-sample unpaired t-test: CaMKIINtide versus Vehicle, P<0.03. This experiment was replicated twice. All data are presented as means±SEM
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Figure 8: T305 autophosphorylation of CaMKII regulates AMPAR protein levels in the ‘learning ganglia’Example GluA1 western blot bands from a paired and CaMKIINtide-treated, a paired and vehicle-treated and a naïve sample, run on the same gel, are shown above the graphs (full-length blot in Supplementary Fig. 7f). Density data obtained from CaMKIINtide (N=8) and vehicle (N=8) samples were normalized to the mean of the density data obtained from naïve samples (N=8), which provided a baseline value of 1. The asterisk indicates significant difference compared to both the naïve baseline and the level measured after CaMKIINtide treatment. One-sample t-tests: CaMKIINtide versus naïve baseline, P=0.41 (n.s.); Vehicle versus baseline, P<0.05. Two-sample unpaired t-test: CaMKIINtide versus Vehicle, P<0.03. This experiment was replicated twice. All data are presented as means±SEM

Mentions: When CaMKIINtide was administered at 6 h post conditioning and immunoblotting tests were performed 30 min later, we found a significant decrease, back to naïve baseline level, in GluA1 expression compared to the vehicle injected paired group in the same experiment (Fig. 8). There was also a statistically significant difference between the normalized data from the CaMKIINtide and vehicle group. This result indicated a link between pT305-CaMKII and the maintenance of increased AMPAR levels. The apparent rapid removal (within 30 min after injection with CaMKIINtide) of previously synthesized AMPARs strongly suggested a role for pT305-CaMKII in the prevention of AMPAR protein degradation.


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)

T305 autophosphorylation of CaMKII regulates AMPAR protein levels in the ‘learning ganglia’Example GluA1 western blot bands from a paired and CaMKIINtide-treated, a paired and vehicle-treated and a naïve sample, run on the same gel, are shown above the graphs (full-length blot in Supplementary Fig. 7f). Density data obtained from CaMKIINtide (N=8) and vehicle (N=8) samples were normalized to the mean of the density data obtained from naïve samples (N=8), which provided a baseline value of 1. The asterisk indicates significant difference compared to both the naïve baseline and the level measured after CaMKIINtide treatment. One-sample t-tests: CaMKIINtide versus naïve baseline, P=0.41 (n.s.); Vehicle versus baseline, P<0.05. Two-sample unpaired t-test: CaMKIINtide versus Vehicle, P<0.03. This experiment was replicated twice. All data are presented as means±SEM
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Figure 8: T305 autophosphorylation of CaMKII regulates AMPAR protein levels in the ‘learning ganglia’Example GluA1 western blot bands from a paired and CaMKIINtide-treated, a paired and vehicle-treated and a naïve sample, run on the same gel, are shown above the graphs (full-length blot in Supplementary Fig. 7f). Density data obtained from CaMKIINtide (N=8) and vehicle (N=8) samples were normalized to the mean of the density data obtained from naïve samples (N=8), which provided a baseline value of 1. The asterisk indicates significant difference compared to both the naïve baseline and the level measured after CaMKIINtide treatment. One-sample t-tests: CaMKIINtide versus naïve baseline, P=0.41 (n.s.); Vehicle versus baseline, P<0.05. Two-sample unpaired t-test: CaMKIINtide versus Vehicle, P<0.03. This experiment was replicated twice. All data are presented as means±SEM
Mentions: When CaMKIINtide was administered at 6 h post conditioning and immunoblotting tests were performed 30 min later, we found a significant decrease, back to naïve baseline level, in GluA1 expression compared to the vehicle injected paired group in the same experiment (Fig. 8). There was also a statistically significant difference between the normalized data from the CaMKIINtide and vehicle group. This result indicated a link between pT305-CaMKII and the maintenance of increased AMPAR levels. The apparent rapid removal (within 30 min after injection with CaMKIINtide) of previously synthesized AMPARs strongly suggested a role for pT305-CaMKII in the prevention of AMPAR protein degradation.

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