Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test

Translational value of mouse models of neuropsychiatric disorders depends heavily on the accuracy with which they replicate symptoms observed in the human population. In mouse models of autism spectrum disorder (ASD) these include, among others, social affiliation, and communication deficits as well as impairments in understanding and perception of others. Most studies addressing these issues in the BTBR T+ Itpr3tf/J mouse, an idiopathic model of ASD, were based on short dyadic interactions of often non-familiar partners placed in a novel environment. In such stressful and variable conditions, the reproducibility of the phenotype was low. Here, we compared physical conditions and the degree of habituation of mice at the time of testing in the three chambered social affiliation task, as well as parameters used to measure social deficits and found that both the level of stress and human bias profoundly affect the results of the test. To minimize these effects, we tested social preference and network dynamics in mice group-housed in the Eco-HAB system. This automated recording allowed for long-lasting monitoring of differences in social repertoire (including interest in social stimuli) in BTBR T+ Itpr3tf/J and normosocial c57BL/6J mice. With these observations we further validate the BTBR T+ Itpr3tf/J mouse as a model for ASD, but at the same time emphasize the need for more ecological testing of social behavior within all constructs of the Systems for Social Processes domain (as defined by the Research Domain Criteria framework).