Behavioural and molecular phenotypes of mouse models for ASD

Autism spectrum disorders (ASD) are more prevalent in male than in female individuals and are characterised by clinical core symptoms such as impaired sociability, verbal communication and ritualistic behaviours. The gene encoding the cytoplasmic FMR1 interacting protein 1 (CYFIP1) has been associated with ASD in humans. At the molecular level, CYFIP1 has been demonstrated to negatively regulate protein synthesis and actin remodelling. At the neuronal level, Cyfip1 haploinsufficiency leads to defects in synaptic plasticity associated with alteration of dendritic spine morphology, two pathophysiological features found in numerous mouse models of ASD. However, the consequences of Cyfip1 deletion at the behavioural level remains unclear, limiting our understanding of the relationship between pathophysiology and behavioural phenotypes. With this study, we aimed to characterise the behavioural phenotype of Cyfip1+/- mice and then to identify associated cellular phenotypes. The results we obtained revealed sex-specific defects in social interest and motor learning. In addition, motor learning deficits were observed in adult Cyfip1+/- mice but not earlier in development. Associated with motor learning deficits, we identified a brain region-specific neuronal phenotype with decreased dendritic spine densities and increased dendritic spine turnover in Cyfip1+/- mice. The dendritic spine formation and the in vivo protein synthesis rate were intact in Cyfip1+/- mice. These results identified behavioural deficits in Cyfip1+/- mice, which relate to symptoms and comorbidities of ASD in human. The cellular phenotypes indicated an alteration of dendritic spine density and spine turnover, a phenotype found in several mouse models of ASD and in humans affected by the condition. Altogether, these findings indicate that Cyfip1+/- mice can represent a valuable model for the study of ASD pathophysiology and in particular the relationship between specific neuronal phenotypes and behavioural alterations