Abstract
Several mouse models of autism spectrum disorder (ASD), including the BTBR T + tf/J (BTBR) inbred strain, display a diverse array of behavioral deficits with particular face validity. Here we propose that phenotyping these preclinical models of ASD should avoid excessive reliance on appearance validity of the behavioral observations. BTBR mice were examined in three non-diagnostic symptoms modalities, beside an anatomical investigation for construct validity. The BTBR strain displayed poor sensorimotor integration as reflected by shorter stride length and greater latency on the balance beam task (BBT) when compared with C57BL/6 (B6) controls. Also, locomotor indices in the open-field task (OFT) revealed that BTBR mice traveled longer distances with a remarkably faster exploration than the B6 group in favor of hyperactivity and impulsiveness. Furthermore, analysis of spatial performance including search strategies in the Morris water task (MWT) indicated spatial impairment in the BTBR strain due to failure to employ spatial strategies during navigation. Quantitative cytoarchitectonics and volumetric examinations also indicated abnormal cortical and subcortical morphology in the BTBR mice. The results are discussed in relation to the neuroanatomical correlates of motor and cognitive impairments in the BTBR strain. We conclude that non-diagnostic autistic-like symptoms in the BTBR mouse strain can be impacted by autism risk factors in a similar way than the traditional diagnostic signs.
Highlights
Autism spectrum disorder (ASD) is typically diagnosed in the early developmental period, and its main diagnostic criteria are behavioral, including a wide range of symptoms in personal, interpersonal, and communicational domains[1]
Despite conceptual and procedural obstacles in developing animal models with core features of autism[4,5], a subset of preclinical models using inbred mouse strains have been proposed in recent years that superficially express traits and behaviors often overlapping with the diagnostic criteria for clinical autism
A significant correlation was found between stride length and latency on the balance beam task (BBT) (B6: rs = −0.614, p ≤ 0.039; BTBR: rs = −0.466, p ≤ 0.041)
Summary
Autism spectrum disorder (ASD) is typically diagnosed in the early developmental period, and its main diagnostic criteria are behavioral, including a wide range of symptoms in personal, interpersonal, and communicational domains[1]. The use of rodents to model complex neuropsychiatric disorders with face validity proved to be challenging and comes with significant difficulties and limitations. Despite conceptual and procedural obstacles in developing animal models with core features of autism[4,5], a subset of preclinical models using inbred mouse strains have been proposed in recent years that superficially express traits and behaviors often overlapping with the diagnostic criteria for clinical autism. Among the existing mouse models, the BTBR T + tf/J (Black and Tan Brachyury, BTBR) inbred mouse strain exhibits behavioral phenotypes analogous to core symptoms of autism, instituting reliable face validity for modeling ASD6–8.
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