title: Catalytically Dead αCaMKII K42M Mutant Acts as a Dominant Negative in the Control of Synaptic Strength.
abstract: During long-term potentiation (LTP) of excitatory synapses, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by Ca(2+) influx through NMDA receptors that potentiate AMPA receptor currents by insertion of additional GluR1-containing receptors at the synapse and by increasing AMPA channel conductance, as well as by stimulating structural changes. CaMKII is also involved in the maintenance of LTP and contributes to maintenance of behavioral sensitization by cocaine or amphetamine. Recent studies show that transient expression of catalytically dead αCaMKII K42M mutant after exposure to amphetamine persistently reverses the behavioral effects of the addiction. A suggested interpretation is that this mutant acts as a dominant negative in the control of synaptic strength, but this interpretation has not been physiologically tested. Here we investigate the effect of αCaMKII K42M mutant expressed in single CA1 pyramidal neurons on basal excitatory neurotransmission in cultured rat hippocampal organotypic slices. The mutant caused nearly 50% reduction in the basal CA3-CA1 transmission, while overexpression of the wild-type αCaMKII had no effect. This result is consistent with the dominant negative hypothesis, but there are complexities. We found that the decrease in basal transmission did not occur when activity in the slices was suppressed after transfection by TTX or when NMDA receptors were blocked by APV. Thus, the dominant negative effect requires neural activity for its expression.
authors.affiliation: Biology Department and Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, United States of America.
authors.forename: Anatoli Y
authors.initials: AY
authors.lastname: Kabakov
authors.affiliation: Biology Department and Volen Center for Complex Systems, Brandeis University, Waltham, Massachusetts, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Lisman
mesh_terms: D000818:Animals; D055162:Biocatalysis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D013569:Synapses / Q000201:enzymology / Q000502:physiology*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2