Memory consolidation induces N-methyl-d-aspartic acid-receptor- and Ca2+/calmodulin-dependent protein kinase II-dependent modifications in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor properties

doi:10.1016/j.neuroscience.2005.08.007

Neuroscience

Volume 136, Issue 2, 2005, Pages 397-403

https://doi.org/10.1016/j.neuroscience.2005.08.007 Get rights and content

Abstract

The N-methyl-d-aspartic acid (NMDA) receptor-dependent activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is necessary for induction of the long-term potentiation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated responses in the CA1 region of the hippocampus, a putative model for learning and memory. We analyzed the interplay among NMDA receptor, CaMKII and AMPA receptor during consolidation of the memory for an inhibitory avoidance learning task in the rat. Bilateral intra-CA1 infusion of the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (AP5) or of the CaMKII inhibitor 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) (KN-93) immediately after step-down inhibitory avoidance training hindered memory consolidation. Learning of the avoidance response induced the NMDA receptor-dependent translocation of αCaMKII to a postsynaptic density-enriched fraction isolated from dorsal CA1 and the autophosphorylation of this kinase at Thr-286. Step-down inhibitory avoidance training increased the quantity of GluR1 and GluR2/3 AMPA receptor subunits and the phosphorylation of GluR1 at Ser-831 but not at Ser-845 in CA1 postsynaptic densities. The intra-CA1 infusion of KN-93 and AP5 blocked the increases in GluR1 and GluR2/3 levels and the phosphorylation of GluR1 brought on by step-down inhibitory avoidance training. Our data suggest that step-down inhibitory avoidance learning promotes the learning-specific and NMDA receptor-dependent activation of CaMKII in the CA1 region of the dorsal hippocampus and that this activation is necessary for phosphorylation and translocation of AMPA receptor to the postsynaptic densities, similarly to what happens during long-term potentiation.

Section snippets

Inhibitory avoidance training

Male Wistar rats (3-month-old, 250–280g) were trained in a IA paradigm, a hippocampal-dependent learning task in which stepping-down from a platform present in a given context is associated with a footshock resulting in an increase in step-down latency (Bernabeu et al 1997, Bevilaqua et al 2003; Cammarota et al., 2004). The IA training apparatus consists of a 50×25×25cm Plexiglas box with a 5cm high, 8cm-wide and 25cm long platform on the left end of a series of bronze bars that make the floor

Results

To investigate whether consolidation of IA memory requires functional NMDAr and CaMKII in the hippocampus, male Wistar rats were trained in IA and, immediately after training, received bilateral infusions of vehicle (saline), the NMDAr antagonist AP5 (25nmol/side) or the CaMKII inhibitor KN-93 (10nmol/side) into the CA1 region of the dorsal hippocampus. Memory retention was evaluated in a non-reinforced test session carried out 24 h later (TT1). AP5 and KN-93 significantly reduced test

Discussion

Our experiments show that the intra-CA1 infusion of AP5 and KN-93 immediately after training hindered retention of IA long-term memory as assessed 24 and 72 h after training (Fig. 1; TT1 and TT2, respectively). We also found that, when submitted to a second training session, those same animals normally acquired the avoidance response and did so as if they had never been trained before (Fig. 1; TT3). These results strongly suggest that inhibition of NMDAr and CaMKII in the CA1 region of the

Conclusion

In conclusion, our results show the necessity of hippocampal NMDAr and CaMKII for the consolidation of IA memory and suggest the existence of a memory-relevant, CaMKII-mediated link between the activation of hippocampal NMDAr and learning-induced modifications of AMPAr properties.

Acknowledgments

This work was supported by grants from ANPCyT and CONICET, Argentine and CNPq, and CAPES, Brazil.

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Behavioural neuroscienceMemory consolidation induces N-methyl-d-aspartic acid-receptor- and Ca2+/calmodulin-dependent protein kinase II-dependent modifications in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor properties

Abstract

Section snippets

Inhibitory avoidance training

Results

Discussion

Conclusion

Acknowledgments

J Biol Chem

Neurobiol Learn Mem

Biophys J

Neuron

J Biol Chem.

Neuron

J Biol Chem

Cell

Neuron

Neurobiol Learn Mem

J Biol Chem

Identification of a regulatory autophosphorylation site adjacent to the inhibitory and calmodulin-binding domains. J Biol Chem

Neuropharmacology

Brain Res

Neuropharmacology

Brain Res

Neuron

Changes in AMPA receptor currents following LTP induction on rat CA1 pyramidal neurones

J Physiol

Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats

Learn Mem

Regulatory phosphorylation of AMPA-type glutamate receptors by CaMKII during long-term potentiation

Science

Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats

Proc Natl Acad Sci U S A

Inhibition of hippocampal Jun N-terminal kinase enhances short-term memory but blocks long-term memory formation and retrieval of an inhibitory avoidance task

Eur J Neurosci

Involvement of the secretory pathway for AMPA receptors in NMDA-induced potentiation in hippocampus

J Neurosci

Learning-specific, time-dependent increases in hippocampal Ca2+/calmodulin-dependent protein kinase II activity and AMPA GluR1 subunit immunoreactivity

Eur J Neurosci

Inhibition of mRNA and protein synthesis in the CA1 region of the dorsal hippocampus blocks reinstallment of an extinguished conditioned fear response

J Neurosci

Isolation and characterization of postsynaptic densities from various brain regionsEnrichment of different types of postsynaptic densities

J Cell Biol

The structure of postsynaptic densities isolated from dog cerebral cortex. I. Overall morphology and protein composition

J Cell Biol

Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

Proc Natl Acad Sci U S A

Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain

J Neurosci

Behavioural neuroscience
Memory consolidation induces N-methyl-d-aspartic acid-receptor- and Ca²⁺/calmodulin-dependent protein kinase II-dependent modifications in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor properties

Learning-specific, time-dependent increases in hippocampal Ca²⁺/calmodulin-dependent protein kinase II activity and AMPA GluR1 subunit immunoreactivity

Ca²⁺/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

Regional distribution of type II Ca²⁺/calmodulin-dependent protein kinase in rat brain