Further dissection of a genomic locus associated with behavioral activity in the Wistar–Kyoto hyperactive rat, an animal model of hyperkinesis

Abstract

Molecular genetic studies of attention-deficit hyperactivity disorder (ADHD) are a major focus of current research since this syndrome has been shown to be highly heritable. 1 Our approach has been to search for quantitative trait loci (QTL) in a genetic animal model of hyperkinesis, the Wistar-Kyoto hyperactive (WKHA) rat, by a whole-genome scan analysis. In a previous article, we reported the detection of a major QTL associated with behavioral activity in an F2 cross between WKHA and Wistar-Kyoto (WKY) rat strains.2 Here, we extend our analysis of this cross by adding new genetic markers, now defining a 10 cM interval on rat chromosome 8 associated with ambulatory and exploratory activities. Then we present a replication of this QTL detection, at least for exploratory activity, by a new genetic mapping analysis of an activity QTL in an F2 cross between the WKHA and Brown Norway (BN) rat strains. Overall, the results provide compelling evidence for the presence of gene(s) influencing activity at this locus. The QTL interval has been refined such that the human orthologous region could be defined and tested in human populations for association with ADHD. Ultimately, the improved dissection of this genomic locus should allow the identification of the causal genes. Molecular Psychiatry (2003Psychiatry ( ) 8, 348-352. doi:10.1038 With the development of a dense genetic map of the rat genome, [3][4][5][6] we were able to test many new microsatellite markers between Wistar-Kyoto hyperactive (WKHA) and Wistar-Kyoto (WKY) rat strains. In total, we tested 142 markers between D8Mgh4 and the telomere of chromosome 8. Only five markers were found to be polymorphic, showing the particularly high level of homology in this region of the genome between the two strains. Our data set was reanalyzed for genetic linkage using these new markers using MAPMAKER program 7 and the results are presented in Figure 1. Maximum LOD score was obtained for ambulatory activity over 1 h in activity cages, LOD ¼ 15.9 with 35% of the phenotypic variance explained by this quantitative trait loci (QTL), with a rise of 7 LOD units compared to our previous report.2 The confidence interval of this QTL is now narrowed to B10 cM between D8Mit15 and ACPH markers. A similar increase was observed for the other traits related to activity including exploratory activity in an open field (LOD maximum ¼ 9.3, 21.6% of the phenotypic variance explained). However, in particular for the latter trait, one can observe two peaks in the LOD score curve. This observation can be interpreted in different ways, one of them being the presence of two linked QTLs. 7Because of the scarcity of polymorphic markers between WKHA and WKY strains, we decided to map activity QTL in a more polymorphic cross. Because the Brown Norway (BN) rat is the most distant genetically from the Wistar-derived strains, 8 we compared its behavioral activity to WKHA and WKY rats. The three parental strains were assessed for their motor activity behavior at approximately 8 and 13 weeks of age. As illu...

Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality

“…The WKY has provided conceptually similar evidence for the involvement of certain genetic loci in behavior. A locus on chromosome 8, confirmed to affect activity in two different crosses, is in the same position as is a loci our cross identified that affects the number of prod approaches in the DB [2,25], and a QTL identified loci affecting prepulse inhibition in a WKY → BN backcross that are in the same position as our Rear1 and Rear3 [26].…”

Intra‐individual variability in genetic and environmental models of attention‐deficit/hyperactivity disorder

“…The Spontaneous Hypertensive Rat (SHR), in particular, expresses all major features of ADHD, including hyperactivity, impulsiveness and inattention [Sagvolden et al, 2005b; Kantak et al, 2008], smaller brain volume [Bendel and Eilam, 1992], sex differences in ADHD‐like phenotype [Sagvolden and Berger, 1996; Berger and Sagvolden, 1998; Bucci et al, 2008] and differences in the expression of genes for catecholaminergic functioning, neuronal metabolism, and ion channels compared to controls [Mill et al, 2005; Russell et al, 2005; Das‐Banerjee et al, 2008]. The Wistar‐Kyoto Hyperactive Rat (WKHA) expresses hyperactivity specifically [Moisan et al, 2003]. Environmental contaminants such as polychlorinated biphenols (PCBs) also induce hyperactivity and impulsiveness, the prenatal period and weaning periods being the most sensitive for neurological damage by PCBs [Pantaleoni et al, 1988; Lilienthal and Winneke, 1991; Morse and Brouwer, 1995].…”

Differential Expression of <b><i>SLC9A9</i></b> and Interacting Molecules in the Hippocampus of Rat Models for Attention Deficit/Hyperactivity Disorder

“…Two inbred substrains have been created from a cross between SHR and WKY/NHsd: the WKHA/N rat with selection for high spontaneous activity and low systolic blood pressure and the WKHT/N with selection for normal spontaneous activity and high systolic blood pressure [14–17]. QTL mapping of the WKHA/N identifying chromosomal regions responsible for the phenotype, revealed a single genome-wide significant QTL on chromosome 8, designated the Act QTL [18, 19]. SLC9A9 is located within this region and close to the highest predicted LOD score.…”