Postnatal reduction of eIF4E overexpression in D1-SPNs ameliorates KCNQ dysfunction, hyperexcitability and ASD-like behaviours

An imbalance between the direct and indirect pathways of the striatum has been implicated in the pathophysiology of ASD, which corresponds with an increase in repetitive behaviours and hyperactivity. The ASD risk gene EIF4E promotes translation, and its overexpression in mice increases repetitive behaviours and hyperactivity. We used the eIF4E-transgenic mouse model of ASD to study cell-type specific disruptions in the direct and indirect pathways using fibre photometry, electrophysiology, conditional gene silencing, and behavioural analysis. We found that direct pathway SPNs activity increased during exploratory behaviour and identified D1-SPN hyperexcitability and reduced KCNQ channel function in striatal slices. Reduction of eIF4E specifically in the D1-SPNs of adult mice normalised KCNQ function, D1-SPN hyperexcitability and ameliorated repetitive and hyperactive behaviours. Our results highlight the critical role of eIF4E in ASD-associated motor behaviours, elucidate cell-specific mechanisms driving hyperactivity and provide new insight into potential therapeutic targets for ASD and other neurodevelopmental disorders. Overall, this study underscores the translational potential of modulating protein synthesis pathways to address core motor symptoms in ASD.