# Epilepsy in focal cortical malformations

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $507,318

## Abstract

Abstract
Tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are caused by mutations
in mTOR pathway genes leading to mTOR hyperactivity, focal malformations of cortical development
(fMCD), and seizures in 80-90% of the patients. The current definitive treatments for epilepsy are
surgical resection or treatment with everolimus, which inhibits mTOR activity (only approved for TSC).
Because both options have severe limitations, there is a major need to better understand the
mechanisms leading to seizures to improve life-long epilepsy treatment in TSC and FCDII. To
investigate such mechanisms, we recently developed a murine model of fMCD-associated epilepsy
that recapitulates the human TSC and FCDII disorders. fMCD are defined by the presence of
misplaced, dysmorphic cortical neurons expressing hyperactive mTOR – for simplicity we will refer to
these as “mutant” neurons. In our model and in human TSC tissue, we made a surprising finding that
mutant neurons express HCN4 channels, which are not normally functionally expressed in cortical
neurons. These data led us to ask several important questions based on the known biology of HCN4
channels: (1) As HCN4 channels are responsible for the pacemaking activity of the heart, can HCN4
channel expression lead to repetitive firing of mutant neurons resulting in seizures? (2) HCN4 is the
most cAMP-sensitive of the four HCN isoforms. Do coincident increases in cAMP (e.g., β-adrenergic
receptors) and hyperpolarization or depolarizations drive HCN4 channel opening and neuronal firing?
(3) HCN4 channel mRNA is expressed in cortical neurons. Is the abnormal HCN4 expression in mutant
neurons due to increased translation via mTOR? (4) Seizures can start at any age in patients that
have been seizure-free for decades, but we do not know why. Can this be explained by worsening of
mTOR hyperactivity with age leading to a progressive increase in HCN4 expression until there is
enough HCN4 channels to depolarize cells and reach firing threshold upon activation? (5) There is no
selective blocker of the HCN4 channel and blocking other HCN channels would have serious central
and peripheral side-effects. Identifying the mechanisms responsible for functional HCN4 expression
may therefore provide alternative therapeutic targets. Do binding partners and/or post-translational
modifications contribute to HCN4 abnormal expression in mutant neurons? We will address these
questions in three aims testing our central hypothesis that abnormal mTOR- and translation-
dependent expression of HCN4 channels leads to repetitive neuronal firing and seizures in TSC and
FCDII. Aim 1: Test the hypothesis that abnormal HCN4 channel expression in murine TSC/FCDII
mutant neurons contribute to neuron excitability and seizure activity. Aim2: Test the hypothesis that
abnormal HCN4 expression is mTOR- and translation-dependent and increases with age and
seizures. Aim 3: Test the hypothesis that HCN4 binding partners and posttrans...

## Key facts

- **NIH application ID:** 10128518
- **Project number:** 5R01NS111980-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Angelique Bordey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,318
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128518

## Citation

> US National Institutes of Health, RePORTER application 10128518, Epilepsy in focal cortical malformations (5R01NS111980-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10128518. Licensed CC0.

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