Social Behavior in Prepubertal Neurexin 1α Deficient Rats: A Model of Neurodevelopmental Disorders

Loss-of-function mutations in the synaptic protein neurexin1 alpha (NRXN1 alpha) are associated with several neurodevelopmental disorders, including autism spectrum disorder (ASD), schizophrenia, and attention-deficit hyperactivity disorder (ADHD), and many of these disorders are defined by core deficits in social cognition. Mouse models of Nrxn1 alpha deficiency are not amenable to studying aspects of social cognition because, in general, mice do not engage in complex social interactions such as social play or prosocial helping behaviors. Rats, on the contrary, engage in these complex, well-characterized social behaviors. Using the Nrxn1(tm1Sage) Sprague Dawley rat, we tested a range of cognitive and social behaviors in juveniles with haplo- or biallelic Nrxn1 alpha mutation. We found a deficit in ultrasonic vocalizations (USVs) of male and female neonatal rats with Nrxn1 alpha deficiency. A male-specific deficit in social play was observed in Nrxn1 alpha-deficient juveniles, although sociability and social discrimination were unaltered. Nurturing behavior induced by exposure to pups was enhanced in male and female juveniles with biallelic Nrxn1 alpha mutation. Performance in tasks of prosocial helping behavior and food retrieval indicated severe deficits in learning and cognition in juveniles with biallelic Nrxn1 alpha mutation, and a less severe deficit in haploinsufficient rats, although Pavlovian learning was altered only in haploinsufficient males. We also observed a male-specific increase in mobility and object investigation in juveniles with complete Nrxn1 alpha deficiency. Together, these observations more fully characterize the Nrxn1(tm1Sage) Sprague Dawley rat as a model for Nrxn1 alpha-related neurodevelopmental disorders, and support a rationale for the juvenile rat as a more appropriate model for disorders that involve core deficits in complex social behaviors.

Automated summary

Loss-of-function mutations in synaptic protein neurexin1 alpha are linked to neurodevelopmental disorders like ASD, schizophrenia, and ADHD, affecting social cognition. Using rats as models, the study found deficits in ultrasonic vocalizations and social play in male rats with Nrxn1 alpha deficiency, while nurturing behavior was enhanced in rats with biallelic mutation. Severe deficits in prosocial helping behavior and learning were seen in rats with biallelic mutation, supporting the rat model for Nrxn1 alpha-related disorders.