# Cross-species modeling of epileptogenesis in KCNT1-associated epilepsy

> **NIH NIH K08** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2021 · $187,306

## Abstract

Project summary
Epilepsy is among the most common childhood neurologic disorders, affecting 40 children per 100,000 in the
US alone. Children with seizure onset before age one have a six-fold increase in early mortality, due in part to
a disproportionately poor response to conventional anticonvulsants. The availability of genetic testing has
dramatically improved etiologic diagnoses of early-onset epilepsy, as ~26% of early-life epilepsy is now
associated with pathogenic genetic mutations in a variety of genes such as ion channels. Yet, precisely-
targeted therapeutic options remain limited. Missense pathogenic variants in KCNT1, a gene encoding a
sodium-activated potassium channel, are causative for ~ 40% of cases of a severe infantile-onset epilepsy
called epilepsy of infancy with migrating focal seizures (EIMFS), suggestive of a strong genotype-phenotype
relationship. As a hallmark of EIMFS is medically-refractory seizures, targeting its pathogenic mechanism is an
opportunity for novel anticonvulsant intervention. The goal of the proposed studies is to define the
pathophysiologic mechanisms that lead to seizures in EIMFS so that anticonvulsant therapies can be rationally
chosen and applied early in the disease course. Aim 1 delineates the cellular mechanisms governing a de
novo KCNT1 gain-of-function variant in human neurons differentiated from patient-derived induced pluripotent
stem cells (iPSCs). We hypothesize that altered KCNT1 channel kinetics result in increased persistent
potassium current, impairing high-frequency firing of inhibitory neurons. Aim 2 combines detailed phenotyping
of a mouse model of KCNT1-associated epilepsy with acute slice electrophysiology of labeled interneuron
subpopulations. We hypothesize that hippocampal interneurons will be differentially affected by a gain-of-
function Kcnt1 knock-in variant, evidenced by decreased action potential firing, with resultant decreased pre-
synaptic GABA release and excessive excitatory neuron bursting. Taken together, these studies will broaden
our understanding of the cellular mechanisms by which KCNT1 mutations contribute to the pathogenesis of
severe childhood epilepsy, laying the groundwork for development of precise pharmacotherapies for EIMFS.
This application is for a K08 Career Development Award for Tracy Gertler, M.D., Ph.D., Child Neurology
Instructor at Lurie Children’s Hospital. To become an independent physician-scientist in the fields of ion
channel physiology and neurogenetics, Dr. Gertler will commit the majority of her post-medical training to
research in genetic epilepsy due to ion channelopathies. The division of pediatric neurology within the
pediatrics department has an unwavering commitment to the career development of the candidate as she
takes advantage of her neurophysiology background and adds training in applied stem cell biology and gene-
editing and phenotyping of animal models of epilepsy under the mentorship of Drs. Alfred L. George, Jr. and
Jennife...

## Key facts

- **NIH application ID:** 10226267
- **Project number:** 5K08NS104237-04
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Tracy S Gertler
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $187,306
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226267

## Citation

> US National Institutes of Health, RePORTER application 10226267, Cross-species modeling of epileptogenesis in KCNT1-associated epilepsy (5K08NS104237-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10226267. Licensed CC0.

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