Mapping murine loci for seizure response to kainic acid

Abstract

Mature DBA/2J (D2) mice are very sensitive to seizures induced by various chemical and physical stimuli, whereas C57BL/6J (B6) mice are relatively seizure resistant. We have conducted a genome-wide search for quantitative trait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F2 intercross population. Parental, F1, and F2 mice (8-10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epilepticus were recorded and used to calculate an overall seizure score. Results of seizure testing indicated that the difference in susceptibility to KA-induced seizures between D2 and B6 mice is a polygenic phenomenon with at least 65% of the variance due to genetic factors. First-pass genome screening (10-cM marker intervals) in F2 progeny (n = 257) documented a QTL of moderate effect on Chromosome (Chr) 1 with a peak LOD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224-D11Mit14), 15 (D15Mit6-D15Mit46) and 18 (D18Mit9-D18Mit144). Multiple locus models generally confirmed the Mapmaker/QTL results and also provided evidence for another QTL on Chr 4 (D4Mit9). Multilocus analysis of seizure severity suggested that additional loci on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contribute to KA-induced seizure response. Overall, our results document a complex genetic determinism for KA-induced seizures in these mouse strains with contributions from as many as eight QTLs.

Acute Cocaine-Induced Seizures Differential Sensitivity of Six Inbred Mouse Strains

“…Confirming several literature reports for sensitivity to KA seizures (Engstrom and Woodbury 1988;Ferraro et al 1995aFerraro et al , 1997, results showed that DBA mice were most sensitive whereas C57 mice were most resistant. A/J mice were more like C57 whereas SJL mice were more like DBA.…”

“…Cocaine was injected ip over a range of doses (50-100 mg/kg) Animal models provide fundamental information regarding seizure mechanisms (Jobe et al 1973;Taylor 1976;Seyfried and Glaser 1985;Golden et al 1991Golden et al , 1995 and studies of inbred murine strains in particular (Engstrom and Woodbury 1988;Kosobud and Crabbe 1990;Kosobud et al 1992;Ferraro et al 1993Ferraro et al , 1997Frankel et al 1995b) have yielded considerable information regarding genetic influences on seizure susceptibility. Paralleling this are studies documenting substantial genetic influences in human epilepsy Leppert et al 1991;Weissbecker et al 1991;Greenberg et al 1992).…”

“…Thus the weighted seizure severity score included measures of both seizure latency and seizure severity. A similar weighted seizure severity score was used in a recent study of kainic acid seizure susceptibility (Ferraro et al 1997). …”

“…The lack of correlation between strain responses to KA and cocaine suggests that the molecular substrates underlying sensitivity to the seizure-inducing effects of these drugs are not identical. Thus, although quantitative trait loci mapping studies have begun to localize genes that influence response in KA seizure (Ferraro et al 1997) and other conventional seizure paradigms, it is likely that QTL mapping for acute cocaine seizures in crosses between C57 and A/J or SJL will provide novel information relevant to the pharmacology of cocaine.In summary, results of this study document substantial strain variation in susceptibility to seizures induced by acute high doses of cocaine. C57 mice were observed to be the most resistant with A/J and SJL mice equally the most susceptible.…”

Characterization and genomic sequence of the murine 60 kD Ro gene

“…The 60 kD Ro gene was mapped to chromosome 1 (cM position 78.7) near the ribosomal protein L7 related sequence 9 gene (Rpl17-9), 20 resistance to mousepox 4 gene (Rmp4), 21 the endogenous ecotropic MuL V 38 gene (Emv 38) 22 and seizure susceptibility 1 gene (Szs1). 23 This region is syntenic to human chromosome 1q31 where the human 60 kD Ro gene has been mapped 24 and is in confirmation of a previous localization of mouse 60 kD Ro. 13,14 Three murine lupus susceptibility loci have been mapped to chromosome 1.…”