National Academy of Sciences, Proceedings of the National Academy of Sciences, 15(118), 2021
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Significance In numerous models of neurodevelopmental disorders and epilepsy, genetic mutations associated with enhanced mTORC1 activity engender an increase in the susceptibility to epileptic seizures. This study shows that the deletion of the mTORC1-downstream translational repressor, 4E-BP2, but not 4E-BP1, promotes epileptogenesis. By deleting 4E-BP2 in different cell types, we reveal that the up-regulation of mTORC1/eIF4E signaling in parvalbumin inhibitory neurons is sufficient to reduce the threshold for the induction of seizures. We conclude that downstream of mTORC1, 4E-BP2 is the main 4E-BP paralog controlling epileptogenesis and propose that parvalbumin inhibitory neurons are a vulnerable cell type in which the aberrant activation of mTORC1-dependent translation contributes to epileptic pathology.