Inhibitory Autophosphorylation of CaMKII Controls PSD Association, Plasticity, and Learning

• Published in: Neuron (Cambridge, Mass.) Vol. 36; no. 3; pp. 493 - 505
• Main Authors: Elgersma, Ype, Fedorov, Nikolai B, Ikonen, Sami, Choi, Esther S, Elgersma, Minetta, Carvalho, Ofelia M, Giese, Karl Peter, Silva, Alcino J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.10.2002; Elsevier Limited
• Subjects: Animal memory; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - deficiency; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Electric Stimulation; Excitatory Amino Acid Antagonists - pharmacology; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Hippocampus - enzymology; Hippocampus - growth & development; Learning - drug effects; Learning - physiology; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Long-Term Synaptic Depression - drug effects; Long-Term Synaptic Depression - genetics; Male; Maze Learning - drug effects; Maze Learning - physiology; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Transgenic; Organ Culture Techniques; Phosphorylation; Presynaptic Terminals - drug effects; Presynaptic Terminals - enzymology; Rodents; Studies; Synaptic Membranes - drug effects; Synaptic Membranes - enzymology; Synaptic Transmission - drug effects; Synaptic Transmission - genetics
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(02)01007-3

To investigate the function of the α calcium-calmodulin-dependent kinase II (αCaMKII) inhibitory autophosphorylation at threonines 305 and/or 306, we generated knockin mice that express αCaMKII that cannot undergo inhibitory phosphorylation. In addition, we generated mice that express the inhibited form of αCaMKII, which resembles the persistently phosphorylated kinase at these sites. Our data demonstrate that blocking inhibitory phosphorylation increases CaMKII in the postsynaptic density (PSD), lowers the threshold for hippocampal long-term potentiation (LTP), and results in hippocampal-dependent learning that seems more rigid and less fine-tuned. Mimicking inhibitory phosphorylation dramatically decreased the association of CaMKII with the PSD and blocked both LTP and learning. These data demonstrate that inhibitory phosphorylation has a critical role in plasticity and learning.