# mTORC1-dependent translational control in developmental epilepsy

> **NIH NIH F32** · YALE UNIVERSITY · 2020 · $67,446

## Abstract

PROJECT SUMMARY
Malformation of cortical development (MCD) is the leading cause of intractable epilepsy in children. Seizures
due to MCD are severe and frequently resistant to antiepileptic drugs, and the only definitive treatment option is
often surgery to remove the abnormal brain regions responsible for seizure generation. These therapeutic
limitations highlight the need for novel approaches to treat MCD-related epilepsy. Recent studies in humans and
animal models have identified pathogenic mutations leading to aberrant hyperactivation of the mechanistic target
of rapamycin complex 1 (mTORC1) signaling pathway in several MCD subtypes that are highly linked to epilepsy,
including tuberous sclerosis complex, focal cortical dysplasia, and hemimegalencephaly, demonstrating an
important role for mTORC1 dysregulation in the pathogenesis of epilepsy. However, the mechanisms by which
mTORC1 dysregulation contributes to epilepsy are not well understood. Since current mTORC1 inhibitors such
as rapamycin and its analogs can have serious side effects, do not fully block all of mTORC1’s functions, and
have limited efficacy, a more specific understanding of the downstream molecular players responsible for
epilepsy development is crucial in order to develop more effective therapies. mTORC1 regulates many cellular
processes, with the best studied function being mRNA cap-dependent translational control. Activation of
mTORC1 promotes mRNA translation via inactivation of the translational suppressor 4EBP. Thus, one working
hypothesis is that upregulated mTORC1-dependent translation leads to exaggerated protein synthesis that
contributes to the neuronal defects underlying epilepsy. Interestingly, normalizing translation via 4EBP
overexpression during cortical development prevented mTORC1-induced cytoarchitectural abnormalities
associated with MCD. However, the effects on neuronal excitability and seizures have not been investigated.
The overall goal of this research is to delineate the contribution of increased mTORC1-dependent translation to
hyperexcitability and seizures (Aim 1) and to identify the specific molecules that are abnormally expressed as a
result of this aberrant increase in translation (Aim 2). A canonical activator of mTORC1, Rheb, will be
constitutively expressed in neurons to mimic the persistent activation of mTORC1 in disease states in mouse
models. Complementing genetic and pharmacological approaches will then be used to target mTORC1-induced
translation and the resulting effects on neuronal excitability and seizures will be assessed. In parallel, mRNAs
that are actively translated in neurons under different conditions of mTORC1 activity will be isolated and identified
by microarray analysis and biochemical validation. The proposed research will advance our understanding of
how altered intracellular signaling pathways and translational control mechanisms modulate neuronal excitability
and seizures and provide mechanistic insights into the pat...

## Key facts

- **NIH application ID:** 9848442
- **Project number:** 5F32HD095567-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** LENA NGUYEN
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848442

## Citation

> US National Institutes of Health, RePORTER application 9848442, mTORC1-dependent translational control in developmental epilepsy (5F32HD095567-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9848442. Licensed CC0.

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