omega-agatoxin-iva and Epilepsy

Inherited errors in ion channel genes comprise the largest subset of monogenic causes of idiopathic epilepsy, and pathogenic variants contribute to genetic risk in the complex inheritance of this common disorder. We generated a digenic mouse model of human idiopathic epilepsy by combining two epilepsy-associated ion channel mutations with mutually opposing excitability defects and overlapping subcellular localization. We found that increasing membrane excitability by removing Shaker-like K(+) channels, which are encoded by the Kcna1 gene, masked the absence epilepsy caused by a P/Q-type Ca(2+) channelopathy due to a missense mutation in the Cacna1a gene. Conversely, decreasing network excitability by impairing Cacna1a Ca(2+)-channel function attenuated limbic seizures and sudden death in Kcna1-null mice. We also identified intermediate excitability phenotypes at the network and axonal levels. Protective interactions between pathogenic ion channel variants may markedly alter the clinical expression of epilepsy, highlighting the need for comprehensive profiling of this candidate gene set to improve the accuracy of genetic risk assessment of this complex disease.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Calcium Channels, P-Type; Calcium Channels, Q-Type; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy; Excitatory Amino Acid Antagonists; Hippocampus; In Vitro Techniques; Kv1.1 Potassium Channel; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nerve Net; omega-Agatoxin IVA; Potassium Chloride

The ability of VSCC antagonists to modulate excitatory amino acid (EAA) release was evaluated by measuring N-methyl-D-aspartate (NMDA) receptor-dependent spontaneous epileptiform discharges in rat cortical wedges. The N-type channel blocker omega-CTX-GVIA (300 nM) was ineffective. The P-type channel blocker omega-Aga-IVA at 300 nM reduced the frequency of discharges by 63%, while 300 nM omega-CTX-MVIIC reduced the frequency by 35%. These results coupled with the absence of NMDA antagonism by omega-Aga-IVA or omega-CTX-MVIIC in the cortical wedge suggest that the VSCCs blocked by these toxins are primarily responsible for mediating impulse dependent EAA release in the rat neocortex.

Topics: Animals; Calcium Channel Blockers; Cerebral Cortex; Electrophysiology; Epilepsy; Evoked Potentials; In Vitro Techniques; Male; omega-Agatoxin IVA; omega-Conotoxins; Peptides; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spider Venoms; Time Factors