Scribble controls social behaviors through the regulation of the ERK/Mnk1 pathway

Social behavior is a basic domain affected in several neurodevelopmental disorders. Indeed, deficits in social interest, interactions and recognition represent core symptoms of Autism Spectrum Disorder but are also found associated with a heterogeneous set of neuropsychiatric and rare disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of open neural tube defect, found at high frequencies in autistic patients, as other congenital anomalies, while the deletions/mutations of the 8q24.3 region encompassing SCRIB genes is associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and ASD-relevant social phenotypes has not been investigated yet. Hence, we performed an extensive behavioral characterization of the circletail line that carries a mutated version of Scrib. Scribcrc/+ mice displayed reduced social interest, lack of preference for social novelty and social reward, and reduced social habituation while other behavioral domains were unaltered. Social deficits were associated with reduced hippocampal volume, upregulation of ERK phosphorylation in specific hippocampal regions, together with increased c-Fos activity in the same brain areas. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a specific link between polarity genes, social behaviors and hippocampal functionality, thus suggesting a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway, in underlying the social deficits induced by SCRIB mutation, thus supporting its relevance as a therapeutic target.