Epilepsia 46 Suppl. 8 :292 (Abst. 3.051 ), 2005
THE ROLE OF ALTERED SODIUM CHANNEL EXPRESSION IN KINDLING EPILEPTOGENESIS
Authors: 1,2,3Angelika Lampert, 1,2,3Joshua P. Klein, 1John F. Mission, 1Maritza Rivera, 1Michael Chen, 1,2,3Bryan C. Hains, 1Akash D. Shah, 4Avis R. Brennan, 1George Varghese, 1-4Stephen G. Waxman, and 1,4Hal Blumenfeld
The molecular mechanism by which amygdala kindling facilitates seizures is unclear. Neuronal voltage-gated sodium channels produce currents which, when abnormally expressed, can result in epileptiform firing patterns. In order to determine the role of altered sodium channel expression in kindling epileptogenesis, we studied the expression of sodium channels in hippocampal neurons, which become hyperexcitable after kindling. To further understand the contribution of altered sodium channel expression to epileptogenesis, we examined heterozygous mice of the med strain, phenotypically indistinguishable from wildtype mice but with only one functional copy of the gene encoding Nav1.6.
48 adult mice were grouped as follows: 12 wildtype sham, 12 wildtype kindled, 12 med sham, 12 med kindled. All mice were implanted with bipolar electrodes in the basolateral amygdala. Kindling was performed twice daily at a stimulus current equal to the afterdischarge threshold until three consecutive Racine class 5 seizures were recorded. Sham mice were implanted and treated identically except only negligible (1ΜA) stimulus was used. All mice were perfused two weeks after kindling, and brains were analyzed by in situ hybridization and immunocytochemistry to identify changes in sodium channel mRNA and protein expression.
Kindled mice showed a significant upregulation of Nav1.6 mRNA and protein in CA3 hippocampal neurons compared to sham kindled mice. Med mice required a significantly greater number of stimulations to complete kindling compared to wildtype mice. Moreover, med mice showed a higher afterdischarge threshold than wildtype mice.
The results of this study indicate that Nav1.6 mRNA and protein is upregulated in CA3 neurons following amygdala kindling. This suggests that overexpression of Nav1.6 could serve as an underlying mechanism for enhanced excitability in kindling. The resistance to kindling exhibited by the heterozygous med mice further implicates Nav1.6 as a mechanistically important component of the kindling process. Further studies are needed to directly measure the possible role of altered sodium currents in enhanced excitability during kindling. (Supported by he Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs, and by grants from the Paralyzed Veterans of America and the United Spinal Association (to S.G.W.); and by NIH NS 049307 and the Blattmachr Fund (to H.B.). J.P.K. is supported by the NIH Medical Scientist Training Program.)
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