Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test

Fragile X syndrome is the most common monogenetic form of intellectual disability and autism. Although the Fmr1 knockout mouse model recapitulates many aspects of the human FXS condition, the establishment of robust social behavioural phenotypes suitable for drug screening has been difficult. Here, we describe a novel social behavioural paradigm, the Automated Tube Test (ATT), for which Fmr1 knockout mice demonstrate a highly reliable and robust phenotype. Fmr1 KO mice show highly dominant behaviour over wild-type littermates in the ATT. Consistent with previous findings, we observed a highly significant, albeit partial, rescue of the altered social behaviour of Fmr1 knockout mice in the ATT, using genetic (mGluR5 deletion) or pharmacological inhibition (mGluR5 antagonist) of mGluR5 signalling independently. Together, our results validate the Automated Tube Test as a robust outcome measure for social behaviour in preclinical research for FXS, and confirm the pathophysiological relevance of mGluR5 signalling. Moreover, our findings highlight the strategy of initiating pharmacological intervention in adulthood as holding significant clinical potential.