N-methyl- d-aspartate receptor dependent transcriptional regulation of two calcium/calmodulin-dependent protein kinase type II isoforms in rodent cerebral cortex

Alpha Calcium/calmodulin-dependent protein kinase type II (CaMKII-α) expression is regulated in an activity-dependent manner, but it is not known whether other CaMKII isoforms (β, δ, and γ) are similarly regulated. We examined the activity-dependent regulation of these CaMKII isoforms in vivo, using a model of generalized seizures caused by i.p. injection of kainic acid. Following seizure induction, CaMKII-α expression was downregulated and CaMKII-δ expression upregulated while CaMKII-β and CaMKII-γ expression was unaffected. A transient downregulation in CaMKII-α and a transient increase in CaMKII-δ occurred throughout neocortex in the same temporal order. Although CaMKII-α mRNA was decreased by seizure activity, the less abundant, alternatively spliced, CaMKII-α33 mRNA was unaffected. Organotypic cortical slice cultures treated with bicuculline and 4-aminopyridine to induce seizure activity also showed a downregulation of CaMKII-α mRNA and an upregulation of CaMKII-δ mRNA. Prior exposure to tetrodotoxin prevented the changes in CaMKII-α and CaMKII-δ mRNA regulation and this was mimicked by d- l-2-amino-5-phosphonovaleric acid, but not by 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline, suggesting that CaMKII-α and CaMKII-δ mRNA expression is regulated in an N-methyl- d-aspartate receptor-dependent manner. Regulation was also transcription dependent. Blocking transcription with actinomycin- d prevented activity-dependent changes in CaMKII-α and CaMKII-δ mRNA, but produced opposite effects on basal transcription, resulting in more stabilized CaMKII-α mRNA and less stabilized CaMKII-δ mRNA. These results reveal unique patterns of seizure-induced alterations in CaMKII mRNAs. Activity-dependent changes in subunit composition could, therefore, differentially influence the functional attributes of the CaMKII holoenzyme.