Inhibition of Calcium/Calmodulin Kinase II Alpha Subunit Expression Results in Epileptiform Activity in Cultured Hippocampal Neurons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 10; pp. 5604 - 5609
• Main Authors: Churn, Severn B., Sombati, Sompong, Jakoi, Emma R., Sievert, Lawrence, DeLorenzo, Robert J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09.05.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Animals, Newborn; Antisense oligonucleotides; Astrocytes - cytology; Astrocytes - physiology; Biological Sciences; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Division - drug effects; Cells, Cultured; Cytarabine - pharmacology; Enzymes; Epilepsy; Epilepsy - enzymology; Epilepsy - physiopathology; Gene Expression Regulation, Enzymologic - drug effects; Hippocampus - physiology; Messenger RNA; Mutation, Missense; Neuroglia - cytology; Neuroglia - drug effects; Neurology; Neurons; Neurons - cytology; Neurons - enzymology; Neurons - physiology; Neuroscience; Nucleotides; Oligodeoxyribonucleotides, Antisense - pharmacology; Oligonucleotides; Phosphorylation; Rats; Seizures
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.080071697

Several models that develop epileptiform discharges and epilepsy have been associated with a decrease in the activity of calmodulin-dependent kinase II. However, none of these studies has demonstrated a causal relationship between a decrease in calcium/calmodulin kinase II activity and the development of seizure activity. The present study was conducted to determine the effect of directly reducing calcium/calmodulin-dependent kinase activity on the development of epileptiform discharges in hippocampal neurons in culture. Complimentary oligonucleotides specific for the α subunit of the calcium/calmodulin kinase were used to decrease the expression of the enzyme. Reduction in kinase expression was confirmed by Western analysis, immunocytochemistry, and exogenous substrate phosphorylation. Increased neuronal excitability and frank epileptiform discharges were observed after a significant reduction in calmodulin kinase II expression. The epileptiform activity was a synchronous event and was not caused by random neuronal firing. Furthermore, the magnitude of decreased kinase expression correlated with the increased neuronal excitability. The data suggest that decreased calmodulin kinase II activity may play a role in epileptogenesis and the long-term plasticity changes associated with the development of pathological seizure activity and epilepsy.