Chronic inhibition of Ca2+/calmodulin kinase II activity in the pilocarpine model of epilepsy

The development of symptomatic epilepsy is a model of long-term plasticity changes in the central nervous system. The rat pilocarpine model of epileps y was utilized to study persistent alterations in calcium/calmodulin-depend ent kinase II (CaM kinase II) activity associated with epileptogenesis. CaM kinase II-dependent substrate phosphorylation and autophosphorylation were significantly inhibited for up to 6 weeks following epileptogenesis in bot h the cortex and hippocampus. bur not in the cerebellum. The net decrease i n CaM kinase II autophosphorylation and substrate phosphorylation was shown to be due to decreased kinase activity and not due to increased phosphatas e activity. The inhibition in CaM kinase II activity and the development of epilepsy were blocked by pretreating seizure rats with MK-801 indicating t hat the long-lasting decrease in CaM kinase II activity was dependent on N- methyl-D-aspartate receptor activation. In addition, the inhibition of CaM kinase II activity was associated in time and regional localization with th e development of spontaneous recurrent seizure activity. The decrease in en zyme activity was not attributed to a decrease in the alpha or beta kinase subunit protein expression level. Thus, the significant inhibition of the e nzyme occurred without changes in kinase protein expression, suggesting a l ong-lasting, post-translational modification of the enzyme. This is the fir st published report of a persistent, post-translational alteration of CaM k inase II activity in a model of epilepsy characterized by spontaneous recur rent seizure activity. (C) 2000 Elsevier Science B.V. All rights reserved.