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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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GluA1 AMPAR activity is necessary for memory consolidation in LymnaeaTreatment with CNQX 6 h after classical conditioning (CS+US) results in impairment of memory at 24 h after training. Timeline for the experiment is shown above the diagram. When tested with the amyl acetate CS at 24 h, the CNQX-treated classically conditioned animals (N=23) show a significantly lower feeding response compared to the vehicle-treated classically conditioned animals (N=21). Naïve animals (N=22) or animals subjected to unpaired training (CS-US interval 1 h, N=20) respond very weakly to the CS. Means±SEM values are shown. Asterisks indicate response levels that are significantly lower than those both in the vehicle-treated and un-treated paired (N=19) group, which have virtually identical high response levels. One-way ANOVA, P<0.0002. Tukey’s tests: CNQX (Paired) versus Vehicle (Paired), Naïve versus Vehicle (Paired) and Naïve versus Paired, all P<0.05; CNQX (Paired) versus Naïve, Paired versus Vehicle (Paired) and Unpaired versus Naïve, all P>0.05). This experiment was replicated twice.
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Figure 1: GluA1 AMPAR activity is necessary for memory consolidation in LymnaeaTreatment with CNQX 6 h after classical conditioning (CS+US) results in impairment of memory at 24 h after training. Timeline for the experiment is shown above the diagram. When tested with the amyl acetate CS at 24 h, the CNQX-treated classically conditioned animals (N=23) show a significantly lower feeding response compared to the vehicle-treated classically conditioned animals (N=21). Naïve animals (N=22) or animals subjected to unpaired training (CS-US interval 1 h, N=20) respond very weakly to the CS. Means±SEM values are shown. Asterisks indicate response levels that are significantly lower than those both in the vehicle-treated and un-treated paired (N=19) group, which have virtually identical high response levels. One-way ANOVA, P<0.0002. Tukey’s tests: CNQX (Paired) versus Vehicle (Paired), Naïve versus Vehicle (Paired) and Naïve versus Paired, all P<0.05; CNQX (Paired) versus Naïve, Paired versus Vehicle (Paired) and Unpaired versus Naïve, all P>0.05). This experiment was replicated twice.

Mentions: Maintained levels of newly synthesized AMPARs have been suggested to contribute to the stabilization of associative long-term memory in mice17. Therefore in our first experiment we tested the hypothesis that AMPARs play a similar role in the consolidation of ALTM in Lymnaea. Specifically, we investigated whether AMPAR activation at 6 h post-training was required for the expression of the classically conditioned response to the conditioned stimulus (CS) at 24 h post-training, i.e., the behavioral readout of ALTM in the paired group. We compared the conditioned response of an AMPAR inhibitor (CNQX) injected and a vehicle injected paired group with each other and against the baseline response in a naïve group (Fig. 1). Additionally, we used a group of animals that were classically conditioned but not treated with CNQX or vehicle (Paired) and another group of animals (Unpaired) that were subjected to an explicitly unpaired training protocol (Fig. 1). The former of these two groups was used for a comparison with the vehicle-injected group, while the latter served as a control for the associative training protocol used in the experiments.


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)

GluA1 AMPAR activity is necessary for memory consolidation in LymnaeaTreatment with CNQX 6 h after classical conditioning (CS+US) results in impairment of memory at 24 h after training. Timeline for the experiment is shown above the diagram. When tested with the amyl acetate CS at 24 h, the CNQX-treated classically conditioned animals (N=23) show a significantly lower feeding response compared to the vehicle-treated classically conditioned animals (N=21). Naïve animals (N=22) or animals subjected to unpaired training (CS-US interval 1 h, N=20) respond very weakly to the CS. Means±SEM values are shown. Asterisks indicate response levels that are significantly lower than those both in the vehicle-treated and un-treated paired (N=19) group, which have virtually identical high response levels. One-way ANOVA, P<0.0002. Tukey’s tests: CNQX (Paired) versus Vehicle (Paired), Naïve versus Vehicle (Paired) and Naïve versus Paired, all P<0.05; CNQX (Paired) versus Naïve, Paired versus Vehicle (Paired) and Unpaired versus Naïve, all P>0.05). This experiment was replicated twice.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4048835&req=5

Figure 1: GluA1 AMPAR activity is necessary for memory consolidation in LymnaeaTreatment with CNQX 6 h after classical conditioning (CS+US) results in impairment of memory at 24 h after training. Timeline for the experiment is shown above the diagram. When tested with the amyl acetate CS at 24 h, the CNQX-treated classically conditioned animals (N=23) show a significantly lower feeding response compared to the vehicle-treated classically conditioned animals (N=21). Naïve animals (N=22) or animals subjected to unpaired training (CS-US interval 1 h, N=20) respond very weakly to the CS. Means±SEM values are shown. Asterisks indicate response levels that are significantly lower than those both in the vehicle-treated and un-treated paired (N=19) group, which have virtually identical high response levels. One-way ANOVA, P<0.0002. Tukey’s tests: CNQX (Paired) versus Vehicle (Paired), Naïve versus Vehicle (Paired) and Naïve versus Paired, all P<0.05; CNQX (Paired) versus Naïve, Paired versus Vehicle (Paired) and Unpaired versus Naïve, all P>0.05). This experiment was replicated twice.
Mentions: Maintained levels of newly synthesized AMPARs have been suggested to contribute to the stabilization of associative long-term memory in mice17. Therefore in our first experiment we tested the hypothesis that AMPARs play a similar role in the consolidation of ALTM in Lymnaea. Specifically, we investigated whether AMPAR activation at 6 h post-training was required for the expression of the classically conditioned response to the conditioned stimulus (CS) at 24 h post-training, i.e., the behavioral readout of ALTM in the paired group. We compared the conditioned response of an AMPAR inhibitor (CNQX) injected and a vehicle injected paired group with each other and against the baseline response in a naïve group (Fig. 1). Additionally, we used a group of animals that were classically conditioned but not treated with CNQX or vehicle (Paired) and another group of animals (Unpaired) that were subjected to an explicitly unpaired training protocol (Fig. 1). The former of these two groups was used for a comparison with the vehicle-injected group, while the latter served as a control for the associative training protocol used in the experiments.

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