Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self‐grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety‐like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3‐hydroxylase, an enzyme‐regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism‐like behavioral phenotypes. Robust and selective social deficits, repetitive self‐grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.

† These authors contributed equally to this manuscriptThe rotorod is commonly used to assess motor ability in mice. We examined a number of inbred strains to determine whether there is genetic variability in rotorod performance and motor learning. Mice received three trials per day for three days in a modified accelerating rotorod paradigm, and active rotation performance was calculated for each day. Male and female 129S1/SvImJ, A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and FVB/NJ mice were tested. Strain and sex differences were observed in motor performance. Motor learning also differed across strains, as some strains showed an improvement in performance over the three days while other strains did not. In certain strains the weight and body length of the mouse correlated with rotorod performance. The role of vision in motor performance on the rotorod was assessed by a comparison of C3H/HeJ mice (with retinal degeneration) and congenic C3A.BLiA-Pde6b + (Pdeb+) mice (without retinal degeneration). The sight-impaired C3H mice stayed on the rotorod longer than did their sighted Pdeb+ partners, although both strains improved across days. Thus, we have demonstrated a genetic component in rotorod performance, and we have shown that factors other than inherent motor ability can contribute to rotorod performance in mice.

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T 1 tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F 1 crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (~29.5 cM) and at 134.5 Mb (~60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.