Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

Abstract

Hyperactivation of mTOR signaling during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests increased cap-dependent translation downstream of mTOR contributes to FMCD formation and seizures. However, whether reducing overactive translation once the developmental pathologies are established reverses neuronal abnormalities and seizures is unknown. Here, we found that the translational repressor 4E-BP1, which is inactivated by mTOR-mediated phosphorylation, is hyperphosphorylated in patient FMCD tissue and in a mouse model of FMCD. Expressing constitutive active 4E-BP1 to repress aberrant translation in juvenile mice with FMCD reduced neuronal cytomegaly and corrected several electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant HCN4 channel expression. This was accompanied by improved cortical spectral activity and decreased seizures. Although mTOR controls multiple pathways, our study shows that targeting 4E-BP1-mediated translation alone is sufficient to alleviate neuronal dysfunction and ongoing epilepsy.

Opto4E-BP, an optogenetic tool for inducible, reversible, and cell type-specific inhibition of translation initiation

“…The versatility of Opto4E-BP allows for its application in studies far beyond the study of memory formation. For example, dysfunctional mTORC1 signaling has been shown to play a role in several types of autism spectrum disorder (ASD), and was found to alter neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy [41][42][43][44][45] . eIF4E has been found to be important for maintenance of circadian rhythms 46-50 and outside of the brain, has been shown to play a role in cancer development 51-54 .…”