A CELL-TYPE SPECIFIC MUTATION OF THE AUTISM CANDIDATE GENE REELIN IN SOMATOSTATIN CORTICAL NEURONS RESULTS IN SELECTIVE AUTISTIC-LIKE BEHAVIOURAL ALTERATIONS IN MICE

Core features of autism spectrum disorder (ASD) include impairments in socio-cognitive functioning and cognitive flexibility, defined as the ability to adapt behaviour to changes in the environment. ASD is one of the most heritable conditions, and among the many genes that are implicated, reelin (RELN) has emerged as a key candidate factor. However, the specific cell types through which it contributes to behavioural dysfunctions remain unclear. We therefore sought to evaluate the function of Reln in a cell type specific manner. To this end, we applied an extensive battery of behavioural paradigms targeting core ASD-relevant domains and examined mice with a reduction or loss of Reln in somatostatin-expressing (SST+) inhibitory cortical interneurons, as compared to littermate controls. We observed that mutant mice showed ASD-relevant behavioural alterations, primarily in the domains of socio-cognitive functioning and cognitive flexibility. Specifically, mutant mice displayed deficits in social recognition of a familiar conspecific, and in discriminating different emotional states of unfamiliar conspecifics. Moreover, mutant mice exhibited reduced cognitive flexibility, as reflected by difficulties in adopting a successful strategy when environmental conditions changed during reversal learning in the Morris Water Maze. Lastly, mutant mice tended to show repetitive patterns of behaviours. Taken together, these findings indicate that impairments in Reln function in cortical SST+ interneurons are sufficient to induce a set of behavioural alterations relevant to ASD. Our study provides new insight into the neuronal circuit mechanisms through which RELN may contribute to neurodevelopmental disorders.