Autism-related behavioral phenotypes in an inbred rat substrain

Abstract

Behavioral and genetic differences among Wistar-Kyoto (WKY) rats from different vendors and different breeders have long been observed, but generally overlooked. In our prior work, we found that two closely related WKY substrains, the WKY/NCrl and WKY/NHsd rats, differ in a small percentage of their genome which appeared to be highly enriched for autism risk genes. Although both substrains have been used widely in studies of hypertension, attention deficit/hyperactivity disorder (ADHD) and depression, they have not been tested for any autism-related behavioral phenotypes. Furthermore, these two substrains have often been used interchangeably in previous studies; no study has systematically examined the phenotypic differences that could be attributed by their small yet potentially meaningful genetic differences. In this paper we compared these two substrains on a battery of neurobehavioral tests. Although two substrains were similar in locomotor activity, WKY/NCrl rats were significantly different from WKY/NHsd rats in the elevated plus maze test, as well as measures of social interaction and ultrasonic vocalization. These strains were also compared with Sprague Dawley (SD) rats, a common outbred strain, and spontaneous hypertensive rats (SHR), an inbred rat model for ADHD and hypertension, which were derived from the same ancestor strain as the WKY strains. Our behavioral findings suggest that WKY/NCrl rats may be useful as a model autism spectrum disorders due to their lower social interest, lower ultrasonic vocalization and higher anxiety levels when WKY/NHsd rats are used as the control strain. Given the small genetic difference between the two inbred substrains, future studies to identify the exact gene and sequence variants that differ between the two may be useful for identifying the genetic mechanisms underlying these behaviors.

Autism spectrum disorder traits in Slc9a9 knock‐out mice

“…Male beddings were used to stimulate adult females to emit USVs. We also reported that WKY/NCrl females had fewer USV calls compared with WKY/NHsd females [Zhang-James et al, 2014]. But because the Slc9a9 mutations are not the only genetic differences between the WKY/Ncrl and WKY/NHsd substrains, we could not definitively implicate Slc9a9 mutations in communication impairments as we could in the present study.…”

“…We previously reported some behavioral phenotypes in the WKY/Ncrl and WKY/NHsd inbred rats [Zhang-James et al, 2014]. These two substrains are genomically similar, having only a 2.5% difference as detected by a 10 K genome-wide SNP array .…”

“…Our previous behavioral studies of rats reported that the WKY/ NCrl and WKY/NHsd substrains behaved similarly in the social novelty preference tests, but that the WKY/NCrl substrain (which carries two nonsynonymous mutations in Slc9a9) had lower social interests compared with the WKY/NHsd substrain [Zhang-James et al, 2014].…”

“…Fifty-three adult mice (Hom ¼ 17, Het ¼ 17, WT ¼ 19, PND60-110) were tested on a modified three-chambered social interaction test [Nadler et al, 2004;Zhang-James et al, 2014]. The apparatus has three chambers (114 Â 51 Â 51 cm 3 , WxLxH) with retractable door between two chambers.…”

Adolescent d -amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

“…Although WKY is frequently used as an inbred control strain for SHR [26], the WKY, particularly from Charles River Laboratories USA, has been used also as a model of anxiety, depression, and more recently, autism spectrum disorder [94,95]. Compared to outbred rat strains, WKY show reduced locomotor activity and social exploratory behavior in the open field test, elevated plus maze, and three-chamber social interaction test, as well as increased learned helplessness and immobility in forced swim and defensive burying paradigms [95][96][97]. Furthermore, in reinforcement-based tasks, WKY earn fewer sucrose pellets than WIS under FR 1 and progressive ratio schedules [98].…”