Early Behavioral Intervention with Juvenile C57BL/6J Cagemates Improves Sociability in the BTBR Mouse Model of Autism

Background: Abnormal reciprocal social interaction is the primary defining symptom of autism. While there is no known effective medical treatment for the autism symptoms, well-structured behavioral interventions produce beneficial effects. Notably, peer-mediated intervention has been found to improve social skills in some children with autism, indicating the important role of frequent social interaction with social peers as part of the behavioral treatment program.  BTBR T+tf/J (BTBR) is an inbred strain of mice that displays prominent social deficits as juveniles and adults, reduced social transmission of food preference, unusual patterns of vocalization, and high levels of repetitive self-grooming, symptoms with considerable face validity to the three diagnostic symptoms of autism. In the social approach test, C57BL/6J (B6) mice exhibit high levels of sociability whereas BTBR mice score poorly, indicating that these two strains might be used to test the effects of peer-mediate behavioral treatments in a mouse model of autism.  Moreover, previous cross-fostering studies showed that BTBR mice raised by C57BL/6J (B6) mothers do not show improved social scores as juveniles and adults, indicating that the early postnatal maternal environment is not sufficient to alter the autism-like behaviors in BTBR.

Objectives: The present study investigates whether living with B6 juveniles in the home cage, during a juvenile to adulthood period in BTBR, could improve social approach behaviors in BTBR. Secondly, this study aims to investigate whether BTBR continue to show improved social behaviors after their former B6 cagemates have been removed. 

Methods:

The intervention procedure began by forming mixed-strain cage mates. Two BTBR and two B6 of the same sex were paired at the time of weaning (postnatal day 21) and allowed to interact freely as cage mates. Control pairings 4 B6 of the same sex in the same home cage during the same period, and 4 BTBR of the same sex in the same home cage during the same period.  Animals were tested for social approach at 8 weeks of age.  Subsequently, after the first social approach test at 8 weeks, BTBR mice from mixed-strain cages were separated from B6 cage mates and tested for social approach again 30 days later.

Results:

Results showed that BTBR exhibited significant sociability after living with B6 cagemates for 40 days, similar to control B6.  BTBR living with BTBR cagemates for 40 days did not show sociability. Moreover, BTBR from mixed-strain cages continued to show significant sociability after living for 30 days without their former B6 cagemates, indicating long-lasting beneficial effects of the juvenile behavioral intervention strategy.

Conclusions:

Findings of the current study indicate that the profound social deficits in BTBR are significantly improved by constant social interaction with highly social B6 “peers”, suggesting that the BTBR mouse model of autism could be used to explore intervention strategies to improve autism-relevant symptoms.