GENETICS | Sixty Years in the Making: A Multifactorial Mouse Model of Seizure Susceptibility

C57BL/6 (B6) and DBA/2 (D2) inbred strains of mice are well known for their difference in seizure susceptibility and have been used together for over 60 years as a model to study epilepsy. The relative resistance of B6 mice to a wide variety of experimentally induced seizures has been studied in relation to the susceptibility of D2 mice in many ways, including direct comparisons of brain anatomy, chemistry, and physiology. Such comparisons have so far failed to provide a comprehensive understanding of the mechanisms responsible for the remarkable strain differences in seizure susceptibility. On the other hand, genetic studies involving quantitative trait loci (QTL) mapping have been more successful in probing the mechanisms underlying this animal model. Currently, it is known that important genetic influences in the model emanate from the telomeric region of chromosome 1 and mid-chromosome 4 and quantitative trait genes (QTG) at these loci have been identified provisionally as Kcnj10 and Mpdz, respectively. Other QTLs in the model have also been identified and work is ongoing to translate them into QTGs, as well as to translate QTGs into clinical studies on epilepsy patients. The recent success in translating provisionally identified Kcnj10 seizure QTG on chromosome 1 into a susceptibility allele for common forms of human epilepsy underscores the potential power of this research strategy. Future work on B6 and D2 mice will allow the model to be exploited further and continue to advance our understanding of the biological mechanisms of seizure susceptibility and epilepsy in humans and aid in the development of new treatments.