Decades of twin, adoption, and family studies have delineated a significant genetic predisposition for psychiatric disorders and epilepsy. Segregation analyses of the inheritance in pedigrees strongly suggest that genetic transmission is multigenic where several genes contribute to a liability for illness. The pursuit of disease loci for bipolar and seizure disorders have underscored the complexity and difficulties in mapping genes for behaviors in humans. As an alternative, we have focused on a mouse model of complex behaviors measuring multiple behavioral dimensions, namely fear-like, exploratory (open field), and generalized seizure behavior. A mouse system offers the advantages of planned matings, good genetic maps, mature genomic resources, and robust transgenic techniques. We propose to positionally clone a major locus affecting several complex behaviors, capitalizing on our recent genetic mapping of a chromosome 10 quantitative trait locus (exq1 QTL) influencing multiple traits, namely open-field behaviors, fear-like behavior, and generalized seizures induced by a beta carboline, methyl-b-carboline-3-carboxylate (b-CCM). Most importantly, this exq1 QTL is a dominantly acting locus and affects multiple traits. Specifically, using strains that differ markedly in their fear-like, exploratory, and drug-induced seizure behavior, we will genetically further localize this chromosome 10 QTL region by generating a series of nested congenic strains. These congenic strains will establish the QTL's range of influence on complex behavior and further delimit the locus. We will positionally clone this exq1 QTL by serially employing recombinational fine mapping of the congenic strains, YAC transgenics, direct selection of cDNA, and evaluation of candidate genes. About 26.9 million Americans suffer from an anxiety disorder, costing an estimated $46.6 billion per year. We interpret rodent exploratory, fear-like, and beta-carboline induced seizure behavior as models of human anxious temperament, anxiety, and seizure vulnerability, respectively. The goal is to understand the biological basis of individual differences in behavior and the etiology of vulnerability to anxiety disorders and seizures in humans. We hypothesize that the characterization of this exq1 locus will delineate a novel mechanism for regulating behavior and neuronal excitability and may lead to a target for rational drug design.
