Neurexin 1 knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia

Rationale Genetic and environmental factors cause neuropsychiatric disorders through complex interactions that are far from understood. Loss-of-function mutations in synaptic proteins like neurexin1 alpha have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), both characterised by problems in social behaviour. Childhood social play behaviour is thought to facilitate social development, and lack of social play may precipitate or exacerbate ASD and SCZ. Objective To test the hypothesis that an environmental insult acts on top of genetic vulnerability to precipitate psychiatric-like phenotypes. To that aim, social behaviour in neurexin1 alpha knockout rats was assessed, with or without deprivation of juvenile social play. We also tested drugs prescribed in ASD or SCZ to assess the relevance of this dual-hit model for these disorders. Results Neurexin1 alpha knockout rats showed an aberrant social phenotype, with high amounts of social play, increased motivation to play, age-inappropriate sexual mounting, and an increase in general activity. Play deprivation subtly altered later social behaviour, but did not affect the phenotype of neurexin1 alpha knockout rats. Risperidone and methylphenidate decreased play behaviour in both wild-type and knockout rats. Amphetamine-induced hyperactivity was exaggerated in neurexin1 alpha knockout rats. Conclusion Deletion of the neurexin1 alpha gene in rats causes exaggerated social play, which is not modified by social play deprivation. This phenotype therefore resembles disinhibited behaviour rather than the social withdrawal seen in ASD and SCZ. The neurexin1 alpha knockout rat could be a model for inappropriate or disinhibited social behaviour seen in childhood mental disorders.