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

Abstract

Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR in the formation of FMCD and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics since these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient FMCD tissue and in a mouse model of FMCD. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by mTOR in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant expression of HCN4 channels. Further, 4E-BP1 expression in juvenile FMCD mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat FMCD-related epilepsy during childhood with potentially long-lasting effects in adults.

Brain somatic mutations as RNA therapeutic targets in neurological disorders

“…Investigating the molecular pathogenesis of FCD, researchers have shown that aberrant hyperactivation of mTOR kinase disrupts autophagy‐mediated ciliogenesis and induces translational dysregulation, thereby resulting in cortical dyslamination and intractable epilepsy, respectively 47–51 . Also, a small number of mutation‐carrying neurons (e.g., 1% of mutated neurons) in the cortex has been found to be sufficient to induce focal epileptogenesis via noncell autonomous mechanisms 52 .…”

“…36,[45][46][47] Investigating the molecular pathogenesis of FCD, researchers have shown that aberrant hyperactivation of mTOR kinase disrupts autophagy-mediated ciliogenesis and induces translational dysregulation, thereby resulting in cortical dyslamination and intractable epilepsy, respectively. [47][48][49][50][51] Also, a small number of mutation-carrying neurons (e.g., 1% of mutated neurons) in the cortex has been found to be sufficient to induce focal epileptogenesis via noncell autonomous mechanisms. 52 Currently, efforts are underway to translate the findings of somatic mutations in FCD into genetic diagnosis and novel therapeutics for FCD patients, including an update to integrated FCD classification with genotyping, 44 detection of low-level somatic mutations in patient's cerebrospinal fluid, 53,54 and a clinical trial of an mTOR inhibitor in FCD type II patients (ClinicalTrials.gov: NCT03198949).…”

Imaging Genetics in Epilepsy: Current Knowledge and New Perspectives

“…However, when and where the brain abnormalities emerge and where changes in the brain fit on the pathway from molecular dysfunction need further investigation. It is essential since early intervention before patients present with symptoms might reverse neuronal abnormalities and seizures (Zhang et al, 2020 ; Nguyen et al, 2021 ). most sporadic focal epilepsies, the underlying mechanisms are unclear.…”

The Coordination of mTOR Signaling and Non-Coding RNA in Regulating Epileptic Neuroinflammation

“…The mammalian target of the rapamycin signaling (mTOR), as the key regulator of protein synthesis and autophagy, plays critical roles in neurophysiological processes such as neural development and brain circuit formation, as well as the continuum of neurological disorders (7)(8)(9)(10)(11)(12). Recently, dysregulation of mTOR signaling has been implicated in infection and inflammatory progresses and acts as an intriguing component of the complex mechanism involved in epileptic neuroinflammation (9,13).…”