Medial prefrontal cortex in social cognition in a rat model of Fragile X syndrome

Abstract

Fragile X syndrome (FXS), caused by the loss of FMRP, is the leading monogenic cause of Autism Spectrum Disorder and Intellectual Disability. Many patients exhibit profound deficits in social cognition, but our incomplete understanding of its pathophysiological underpinnings has thus far hindered the development of effective treatment strategies. The mPFC forms a central component of the brain’s social circuit and preliminary evidence has begun linking altered mPFC function to autistic like social impairments in FXS.

The aim of this work was to understand whether aberrant social behaviour, resulting from the loss of FMRP, is associated with distinct changes at the level of mPFC microcircuit function. To approach this aim we performed micro endoscopic calcium imaging of mPFC excitatory neurons in FMR1 KO rats undergoing a social interaction task.

Behavioural observations from the social interaction task revealed normal levels of social preference and preference for social novelty of FMR1 KO rats. These results add to the growing body of evidence highlighting the limited potential of rodent models and conventional behavioural assays for modelling the social phenotypes of FXS. Our imaging observations from a small number of animals suggest that the mPFC forms accurate representations of social task-context and individual interaction dyads. At the single cell level, we report opposing ensembles of functionally defined neurons that exhibit increased or decreased activity, specifically, during periods of social interaction. The wider mPFC principal cell population accurately represented the ongoing social behaviour. Collectively, these observations firmly align with recent accounts implicating the mPFC in real-time encoding social experiences.

Future translational work will need to identify improved ways of modelling the social phenotype of human FXS patients, either through the use of alternative model organisms or novel behavioural paradigms. In addition, research aimed at unravelling the neural correlates of social cognition should focus on the mechanisms that give rise to our internal representations of social experience.