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

An imbalance between the direct and indirect pathways of the striatum has been linked to the pathophysiology of autism spectrum disorder (ASD), manifesting as repetitive behaviours and hyperactivity. We have investigated cell-specific dysfunctions in spiny projection neurons (SPNs) in a mouse model of ASD characterised by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation. eIF4E-TG mice, which exhibit ASD-like motor behaviours, were examined using a combination of fibre photometry, electrophysiology, conditional gene silencing, and behavioural assays. Direct pathway SPNs showed elevated activity during exploratory behaviour, along with hyperexcitability and reduced KCNQ potassium channel function in striatal slices. Conditional reduction of eIF4E in direct pathway SPNs of adult mice ameliorated KCNQ channel function, reduced excitability, and attenuated repetitive and hyperactive behaviours. These findings provide novel evidence that eIF4E-dependent translational dysregulation is associated with altered potassium channel function in direct pathway SPNs, and that postnatal reduction of eIF4E can mitigate motor phenotypes relevant to ASD in a cell-type-specific manner. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06115-2.