Research reportAssessing autism-like behavior in mice: Variations in social interactions among inbred strains
Introduction
At least one child out of every 1000 born in the United States will at a later developmental time point be diagnosed with autism spectrum disorder. This estimate may be very conservative; in fact, some recent estimates are as high as 7 per 1000 [22], [26], [56]. Autism spectrum disorders have recently been equated to Alzheimer's disease in terms of “patient years” that they represent to our society [27]. First identified and described in the 1940s [3], [30], autism is classified as one of the pervasive developmental disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), with clinical symptoms including impairments in reciprocal social interaction, restlessness and distraction, difficulty with language, and repetitive and stereotyped motor behaviors [1]. The clinical phenotype of autism is complex and variable, making a simple therapy or solution problematic. Instead, a combination of therapeutic approaches may be the best solution for such a diverse phenotype. A number of brain regions are thought to be involved in this disorder, including the cerebellum, hippocampus, amygdala, basal ganglia, corpus callosum, and brainstem [4], [15], [44], [53], and both the serotonergic and glutaminergic systems may play roles [14], [16]. Unfortunately, the etiology of the disorder is still far from clear.
Autism is a complex disorder, likely to be influenced by a combination of genetic and environmental factors. Elucidation of autism-related genes is important for potential therapeutic interventions and, eventually, a cure. The first evidence for a genetic role in autism came from an epidemiological study of affected twins [24]. More recently attention has been focused on attempting to define the genetic component of autism [2], [25], [31], [33], [36]. A better understanding of the relationship between phenotype and genotype will provide new insights into the mechanisms involved. The use of non-human models of autism will be of great importance for determining the genotype–phenotype relationship, and for therapeutic testing. Advanced transgenic and recombinant technologies, and the recent sequencing of the mouse genome, have made the mouse the model of choice for many geneticists. While not all human behaviors can be easily translated to the mouse, we can, through careful operational definitions of the behavior being studied, use the mouse model to elucidate some of the fundamental elements of complex behaviors in humans. These components may not be disorder-specific (i.e., there may not be a perfect mouse model for disorders such as autism); however, we can use specific genetic findings in the mouse to search for candidate loci for human disorders [13], [51]. With careful dissection of behavior, and with a thorough understanding of the components of the behavioral assay being utilized, we can enhance our potential to produce mouse models of social behavioral abnormalities such as autism [40]. In fact, most of the core symptoms of autism spectrum disorder can be evaluated in the mouse through an intensive battery of tests [20].
On 4th December 2000, experts from the fields of autism, mouse genetics, and mouse behavior met at the Jackson Laboratory, Bar Harbor, ME, to discuss the utility of mouse models of autism. The consensus from that meeting was that mouse models of autism can make a significant contribution to our understanding of this complex disorder, although if we are to maximize the effectiveness of mouse models, we need to know more about the genetics involved [29]. Thus far, the effects of ablation or mutation of a number of genes have been examined in mouse models of autism, with mixed phenotypic results [23], [34], [35], [39], [49]. However, there is a great need for additional mouse models, especially those that are based on naturally occurring differences among groups of mice, i.e., differences among inbred strains. Crawley and colleagues [43] have recently developed a social novelty/sociability automated assay that they are using to examine autism-like behaviors in inbred strains of mice. Their studies illustrate that variability in social responsiveness exists among some of the most common inbred strains, with A/J, BALBcByJ, and BTBR T + tf/J strains being less socially responsive [41], [42]. Brodkin and colleagues [12], [50] describe the BALB/cJ strain as displaying low levels of sociability, in contrast to strains such as C57BL/6J. Our laboratory has been examining inbred strain behavior variability with a number of assays, including open field, fear conditioning, food preference, rotorod, and zero maze [6], [8], [10], [17], [37]. Since inbred mouse strain differences have been established for many behaviors, we decided to examine social behavior across a set of common inbred strains. This inbred strain survey is a first step in determining which of these strains will be the subject of future genetics research.
Section snippets
Mice
Male and female breeding pairs from seven inbred strains, 129S1/SvImJ (129S1), A/J (A), BALBcBy/J (CBy), C57BL/6J (B6), BTBR T + tf/J (BTBR), DBA/2J (D2), and FVB/NJ (FVB), were purchased from the Jackson Laboratory (Bar Harbor, ME) and maintained in our colony at the Wadsworth Center. Male offspring of these breeders were used in all studies and were socially naïve to one another before the onset of testing. At weaning, mice were housed in same-sex groups of 2–4 per cage, at a temperature of 21 ± 2
Study 1
There were significant differences in the amount of time spent engaged in social interactions (F(4, 25) = 8.441, p = 0.0002; see Fig. 1), with BTBR mice spending the least and FVB spending the most time engaged in social behavior, among the five strains (all comparisons p < 0.05; except the comparison between B6 and BTBR, where p < 0.12). When we examined specific types of social behavior, it was clear that some behaviors were more common than others and were seen in all strains tested, whereas for
General discussion
It is clear from these studies that inbred mouse strains can differ markedly in their levels of social behavior. This conclusion is in agreement with findings of previous studies [41], [50]. Some strains (e.g., FVB) are very social, whereas others (e.g., A, BTBR) are not. Furthermore, some social behaviors, like sniffing, are common in all strains, although the time spent engaged in this behavior varies across strains. Other social behaviors (e.g., mounting of same-sex mouse) are relatively
Acknowledgements
This work was supported by NIH grants MH067850 and MH068013 to Valerie Bolivar. The authors would like to thank Rene Macy and Alexis Santiago for technical assistance.
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