International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

POSTER 52 - GENE INTERACTIONS BETWEEN CALCIUM CHANNELS IN THE PATHOGENESIS OF ABSENCE EPILEPSY

Dr. Hee-Sup Shin
Korea Institute of Science and Technology
P.O. Box 131, Cheongryang
Seoul 130-650
Korea (South)

Co-Authors: 1) Kim D, 1) Song I, 1) Keum S, 1) Kim SS, 1) McEnery MW, 2) Jeong M, 2) Lee TH
Institutions: 1)Case Western Reserve Univ. School of Medicine, 2)Pohang University of Science & Technology

Complex interactions among multiple components contribute to the genesis of absence seizures, which are characterized by a brief loss of consciousness associated with an EEG recording of bilaterally synchronous spike-and-wave discharges (SWDs). We tried to define the role of calcium channels in the SWDs seizures by mutating multiple calcium channel isotypes. First, we found that knockout mice for the a1A subunit of high-voltage-activated (HVA) Ca2+ channels (a1A -/-) show 4-5 Hz SWDs with behavioral absence seizures. The cellular mechanisms underlying the absence seizures were examined by physiological analysis of the thalamic relay neurons. Whole-cell patch clamp analysis showed that low-voltage-activated (LVA) T-type calcium currents were increased whereas HVA currents were decreased in the mutant cells, suggesting a role of T-type calcium channels in the genesis of absence seizures. Next, we generated a knockout of the a1G subunit of T-type channels (a1G-/-). The a1G-/- mice were resistant to the generation of SWDs in response to GABAB receptor activation. To examine gene interactions between the two isotypes, the double mutants were obtained. EEG analysis showed that SWDs of a1A-/- disappeared in the double mutants, indicating a genetic suppression of a1A-/- by a 1G-/-. We conclude that the altered profile of LVA/HVA currents, lead to the pathological synchronizing condition in the thalamocortical network, resulting in absence seizures.