Abstracts

Three independent QTL mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice detected a significant effect originating from chromosome 5 in the interval between 20 and 45 cM. The mapping phenotypes involved 1) responsiveness to kainic acid, 2) responsiveness to pentylenetetrazol (PTZ) and 3) determination of maximal electroshock seizure threshold (MEST). In order to confirm the presence and position of the chromosome 5 QTL (Szs11), reciprocal congenic strains between B6 and D2 mice were created using a classical DNA marker-assisted backcross breeding strategy., A genomic interval delimited by marker D5Mit75 (20 cM) proximally and D5Mit403 (56 cM) distally was introgressed for 10 generations and the interval made homozygous by brother-sister mating. MEST was assesed in congenic and parental mice at the age of 8-12 weeks using a classical design in which mice are given one shock per day (starting at 20 mA with a daily incremental increase of 2 mA) until a maximal seizure (hind limb extension) is elicited. PTZ testing was conducted using a single injection of drug (80 mg/kg, sc) and a 30 minute observation period for scoring seizures., Results of MEST studies revealed significant differences for congenic strains compared to background parental strains. Mean ([plusmn] SD) MEST (given in mAmperes) for B6.D2-Szs11 mice (males: 65 [plusmn] 6; females: 60 [plusmn] 6) was significantly less than B6 (males: 72 [plusmn] 6; females 66 [plusmn] 5; P[lt]0.01, N=16-24, ANOVA, Neuman-Keuls). Conversely, Mean MEST for D2.B6-Szs11 mice (males: 30 [plusmn] 4; females: 26 [plusmn] 3) was significantly greater than D2 (males: 24 [plusmn] 2; females: 22 [plusmn] 2; P[lt]0.05, N=8-16). Results of PTZ testing were consistent with MEST results and documented a modest but significant effect of the congenic interval in both reciprocal strains., We conclude that the Szs11 gene(s) resides in the interval between D5Mit75 and D5Mit403 and that it determines in part the responsiveness of B6 and D2 mice in diverse seizure paradigms. If a single gene underlies Szs11, its ability to influence susceptibility to seizures elicited by different mechanisms suggests that it may be a gene of fundamental importance in the regulation of neuronal excitability. Identification of such genes could lead to new insight into the pathogenesis and treatment of epilepsy., (Supported by NS040554 (TNF).)