ArticlePLoS biology2021
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 52 citations in OpenAlex.
- Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.Neuroscience and biobehavioral reviews · 2026Review
- Effect Modification of Alcohol Use on Epilepsy: NHIS Longitudinal Study.Biomedicines · 2026Article
- Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.Stem cell reports · 2026Article
- Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation.Scientific reports · 2026Article
- Seizure occurrence in FCD type II is predicted by lesion position and linked to cytoarchitectural alterations.Acta neuropathologica communications · 2025Article
- Ablation of dysmorphic neurons is a safe and effective treatment for focal cortical dysplasia II.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Increased Complement C4 in a Sparse Neuronal Subset Induces Network-Wide Transcriptomic Alterations in the Prefrontal Cortex.bioRxiv : the preprint server for biology · 2025Article
- Developmental mechanisms underlying pediatric epilepsy.Frontiers in neurology · 2025Review
- Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction.Acta neuropathologica communications · 2024Article
- Reducing Filamin A Restores Cortical Synaptic Connectivity and Early Social Communication Following Cellular Mosaicism in Autism Spectrum Disorder Pathways.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2024Article
- The mTOR pathway geneseLife · 2024Article
- Anti-seizure gene therapy for focal cortical dysplasia.Brain : a journal of neurology · 2024Article
- The mTOR pathway genesbioRxiv : the preprint server for biology · 2024Article
- autoMEA: machine learning-based burst detection for multi-electrode array datasets.Frontiers in neuroscience · 2024Article
- Functional profile of perilesional gray matter in focal cortical dysplasia: an fMRI study.Frontiers in neuroscience · 2024Article
- The alteration of cortical microstructure similarity in drug-resistant epilepsy correlated with mTOR pathway genes.EBioMedicine · 2023Article
- PathogenicNeurology · 2023Article
- Involvement of the G-Protein-Coupled Estrogen Receptor-1 (GPER) Signaling Pathway in Neurodegenerative Disorders: A Review.Cellular and molecular neurobiology · 2023Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.