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The Journal of Neuroscience, May 15, 1999, 19(10):3731-3738

Mapping Quantitative Trait Loci for Seizure Response to a GABA_A Receptor Inverse Agonist in Mice

Howard K. Gershenfeld¹, Paul E. Neumann², Xiaohua Li¹, Pamela L. St. Jean³, and Steven M. Paul^{4, 5}

¹ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8898, ² Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7, ³ Glaxo Wellcome Research, Inc., Research Triangle Park, North Carolina 27514, ⁴ Lilly Research Laboratory, Indianapolis, Indiana 46285, and ⁵ Departments of Psychiatry, Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202

To define the genetic contributions affecting individual differences in seizure threshold, a  carboline [methyl--carboline-3-carboxylate (-CCM)]-induced model of generalized seizures was genetically dissected in mice. -CCM is a GABA_A receptor inverse agonist and convulsant. By measuring the latency to generalized seizures after -CCM administration to A/J and C57BL6/J mice and their progeny, we estimated a heritability of 0.28 ± 0.10. A genome wide screen in an F2 population of these parental strains (n = 273) mapped quantitative trait loci (QTLs) on proximal chromosome 7 [logarithm of the likelihood for linkage (LOD) = 3.71] and distal chromosome 10 (LOD = 4.29) for seizure susceptibility, explaining ~22 and 25%, respectively, of the genetic variance for this seizure trait. The best fitting logistic regression model suggests that the A/J allele at each locus increases the likelihood of seizures approximately threefold. In a subsequent backcross population (n = 223), we mapped QTLs on distal chromosome 4 (LOD = 2.88) and confirmed the distal chromosome 10 QTLs (LOD = 4.36). In the backcross, the C57BL/6J allele of the chromosome 10 QTL decreases the risk of seizures approximately twofold. These QTLs may ultimately lead to the identification of genes influencing individual differences in seizure threshold in mice and the discovery of novel anticonvulsant agents. The colocalization on distal chromosome 10 of a -CCM susceptibility QTL and a QTL for open field ambulation and vertical movement suggests the existence of a single, pleiotropic locus, which we have named Exq1.

Key words: quantitative trait locus (QTL); epilepsy; seizure; -carboline; open field; individual differences

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19103731-08$05.00/0

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