Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity, and learning.
To investigate the function of the alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) inhibitory autophosphorylation at threonines 305 and/or 306, we generated knockin mice that express alphaCaMKII that cannot undergo inhibitory phosphorylation. In addition, we generated mice that express the inhibited form of alphaCaMKII, 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.
Elgersma
Ype
Y
Department of Neurobiology, Department of Psychiatry, Department of Psychology, Brain Research Institute, University of California, Los Angeles, CA 90095, USA.
Fedorov
Nikolai B
NB
Ikonen
Sami
S
Choi
Esther S
ES
Elgersma
Minetta
M
Carvalho
Ofelia M
OM
Giese
Karl Peter
KP
Silva
Alcino J
AJ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency* / Q000235:genetics; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000201:enzymology* / Q000254:growth & development; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology*; D013570:Synaptic Membranes / Q000187:drug effects / Q000201:enzymology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*
D018691:Excitatory Amino Acid Antagonists; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases