Abstracts

RATIONALE: Status Epilepticus has been shown to cause a significant inhibition of both CaM kinase II activity and GABAA receptor function in a duration-dependent manner. Previous studies by this laboratory and others have shown that CaM kinase II activation can positively modulate both GABAAR agonist binding and agonist-induced currents. Therefore, this study was designed to determine whether or not addition of exogenous CaM kinase II could reverse some of the SE-induced inhibition of GABAAR function. METHODS: SE was induced in hippocampal neurons in culture by 3 hr exposure to 0-Mg media. Autoactivated (thio-phosphorylated), truncated CaM kinase II a subunit (1.2 U/ml) was injected into control and SE neurons to determine the effect on GABAA currents. Heat-inactivated kinase was used as a control. Whole cell voltage clamp recordings were performed and response to GABA application recorded and quantified. RESULTS: SE caused a 50% decrease in GABAA current when compared to sham control cultures. Inclusion of autoactivated CaM kinase II a subunit in 0Mg-treated neurons resulted in a 3 to 4-fold increase in GABA-evoked currents. Injection of autoactivated CaM kinase II a subunit into control neurons resulted in a 45% increase in GABAA response. Heat-inactivated kinase did not significantly alter GABAA currents in either control or SE neurons. CONCLUSIONS: The results suggest that CaM kinase II injection into "epileptic" neurons resulted in restoration of GABAAR currents to near control levels. The data support the hypothesis that SE-induced inhibition of CaM kinase II activity may play a causal role in SE-induced epileptogenesis.