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NEUROPHARMACOLOGY

Altered Calcium/Calmodulin Kinase II Activity Changes Calcium Homeostasis That Underlies Epileptiform Activity in Hippocampal Neurons in Culture

Department of Anatomy and Neurobiology (D.S.C., S.N.H.), Department of Pharmacology and Toxicology (R.J.D.), Department of Neurology (R.E.B., S.S., L.S.D., R.J.D.), and Department of Biochemistry and Molecular Biophysics (R.J.D.), Virginia Commonwealth University, Richmond, Virginia

Epilepsy is characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. A decrease in calcium/calmodulin-dependent protein kinase II (CaMK-II) activity has been shown to occur with the development of SREDs in a hippocampal neuronal culture model of acquired epilepsy, and altered calcium (Ca²⁺) homeostasis has been implicated in the development of SREDs. Using antisense oligonucleotides, this study was conducted to determine whether selective suppression of CaMK-II activity, with subsequent induction of SREDs, was associated with altered Ca²⁺ homeostasis in hippocampal neurons in culture. Antisense knockdown resulted in the development of SREDs and a decrease in both immunocytochemical staining and enzyme activity of CaMK-II. Evaluation of [Ca²⁺]_i using Fura indicators revealed that antisense-treated neurons manifested increased basal [Ca²⁺]_i, whereas missense-treated neurons showed no change in basal [Ca²⁺]_i. Antisense suppression of CaMK-II was also associated with an inability of neurons to restore a Ca²⁺ load. Upon removal of oligonucleotide treatment, CaMK-II suppression and Ca²⁺ homeostasis recovered to control levels and SREDs were abolished. To our knowledge, the results demonstrate the first evidence that selective suppression of CaMK-II activity results in alterations in Ca²⁺ homeostasis and the development of SREDs in hippocampal neurons and suggest that CaMK-II suppression may be causing epileptogenesis by altering Ca²⁺ homeostatic mechanisms.

Address correspondence to: Dr. Robert J. DeLorenzo, Virginia Commonwealth University School of Medicine, P.O. Box 980599, Richmond, VA 23298. E-mail: rjdeloren{at}hsc.vcu.edu