Dissertation Defense: Impact of the Kcnt1 R428Q Mutation on Neuronal Subtype Excitability and Therapeutic Approaches in a Mouse Model
Dissertation Defense
Impact of the Kcnt1 R428Q Mutation on Neuronal Subtype Excitability and Therapeutic Approaches in a Mouse Model
Mona Safari
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Weston Lab, Fralin Biomedical Research Institute at VTC
June 29, 2026 at 11 a.m.
About this Dissertation
Gain-of-function (GOF) mutations in KCNT1, encoding the sodium-activated potassium channel KNa1.1, are associated with severe developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). However, the cell-type–specific mechanisms underlying seizure generation and effective targeted therapies remain unclear. Here, Safari, mentored by Matt Weston, generated a mouse model carrying the Kcnt1-R409Q (human R428Q) mutation and found that this GOF variant selectively reduces the excitability of somatostatin (SST) interneurons, while excitatory neurons and parvalbumin (PV) interneurons remain largely unaffected. Selective expression of the mutation in medial ganglionic eminence (MGE)-derived interneurons was sufficient to recapitulate the seizure phenotype. Safari next tested a selective, high-potency KCNT1 inhibitor and found that it robustly suppressed seizures in vivo. Electrophysiological recordings revealed that KCNT1 inhibition increased interneuron excitability, reversing the hypoexcitability observed in mutant mice, while excitatory neuron function remained unchanged. To assess whether this approach extends to other channelopathies, Safari evaluated the compound in a Dravet syndrome model caused by loss-of-function of the NaV1.1 sodium channel (SCN1A). Treatment significantly reduced seizure frequency, decreased SUDEP incidence, and improved survival. At the cellular level, KCNT1 inhibition enhanced PV interneuron excitability, indicating a shared mechanism across distinct genetic epilepsies. Together, these findings identify KCNT1 as a key regulator of neuronal excitability and demonstrate that its inhibition can modulate circuit function and suppress seizures. This work highlights the potential of KCNT1 inhibition as a therapeutic approach for multiple forms of drug-resistant epilepsy.
More About the Candidate and Project
Education
Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate
Alborz University of Medical Sciences, B.S., Anesthesiology
Training
Graduate Research Assistant, Weston Lab, Fralin Biomedical Research Institute at VTC
Mentors
Matthew Weston, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
Committee Members
- Sharon Swanger, Ph.D., Assistant Professor, Fralin Biomedical Research Institute at VTC
- Yuchin Albert Pan, Ph.D., Associate Professor, Commonwealth Research Commercialization Fund Eminent Research Scholar in Developmental Neuroscience, Fralin Biomedical Research Institute at VTC
- Alexandra DiFeliceantonio, Ph.D., Associate Professor, Interim Co-director, Center for Health Behaviors Research, Fralin Biomedical Research Institute at VTC
Publications
Mona Safari, Rutvi Desai, Harbal Rai, Tyler J Roberts, Rabeya Khondaker, Julia Smith, Sharon A Swanger (2026), Input-and cell-type-specific developmental alterations to thalamic synapses in a Dravet syndrome mouse model. https://doi.org/10.64898/2026.02.12.705567
Mona Safari, Matthew C Weston (2025), Decomposing SV2A Function and Dysfunction one Neuron at a Time. https://doi.org/10.1177/15357597251352976
Cullen, E., Safari, M., Mittelstadt, I., & Weston, M. (2024). Hyperactivity of mTORC1- and mTORC2-dependent signaling mediates epilepsy downstream of somatic PTEN loss. eLife, 12. https://doi.org/10.7554/eLife.91323.3
Amy N. Shore, Keyong Li, Mona Safari, Alshaima’a M. Qunies, Brittany D. Spitznagel, C. David
Weaver, Kyle A. Emmitte, Wayne N. Frankel, and Matthew C. Weston (2024). Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on SST- and PV-expressing cortical GABAergic neurons. https://doi.org/10.7554/eLife.92915.4
Studtmann, C., Ladislav, M., Safari, M., Khondaker, R., Chen, Y., Vaughan, G., Topolski, M., Tomović, E., Balik, A., & Swanger, S. (2023). Ventral posterolateral and ventral posteromedial thalamocortical neurons have distinct physiological properties. Journalof neurophysiology, 130. https://doi.org/10.1152/jn.00525.2022
Carleigh Studtmann, Marek Ladislav, Mackenzie A. Topolski, Mona Safari, Sharon A. Swanger, (2022) NaV1.1 haploinsufficiency impairs glutamatergic and GABAergic neuron function in the thalamus, Neurobiology of Disease, Volume 167, 2022, 105672, ISSN 0969-9961, https://doi.org/10.1016/j.nbd.2022.105672.
Oral Presentations
Oct 2026, Mona Safari, Matthew C. Weston. "Impact of KCNT1 R428Q Mutation on Neuronal Subtype Excitability in a Mouse Model. " Research in Progress Seminar, Fralin Biomedical Research Institute, Virginia Tech.
Aug 2024, Mona Safari, Matthew C. Weston. "Impact of KCNT1 R428Q Mutation on Neuronal Excitability and Seizure Activity in a Mouse Model." Center for Neurobiology Research, Fralin Biomedical Research Institute, Virginia Tech.
Nov 2022, Mona Safari and Sharon A. Swanger. "How synapse dysfunction develops in a Dravet-Syndrome mouse model." Research in Progress Seminar, Fralin Biomedical Research Institute, Virginia Tech.
Poster Presentations
International Conferences
Nov 2025, Mona Safari, Amy Shore, Gouen Jang, and Matthew C. Weston. "Impact of KCNT1 R428Q Mutation on Neuronal Subtype Excitability in a Mouse Model." Society for Neuroscience, San Diego, California.
Dec 2024, Mona Safari, Erin Cullen, Amy Shore, and Matthew C. Weston. "Altered Cellular Excitability in a KCNT1 R428Q Mouse Model of Severe Epilepsy." American Epilepsy Society Annual Meeting, Los Angeles, California.
Dec 2022, Mona Safari and Sharon A. Swanger. "Development of thalamic synapse alterations in a Dravet syndrome mouse model." American Epilepsy Society Annual Meeting, Nashville, Tennessee.
Regional Conferences
Aug 2025, Mona Safari, Amy Shore, and Matthew C. Weston. " Effects of KCNT1 Blockade on Neuronal Subtype Excitability in a KCNT1 Gain-of-Function Mouse Model " Translational Biology, Medicine, and Health Open House, Fralin Biomedical Research Institute, Virginia Tech.
Apr 2024, Mona Safari, Amy Shore, Erin Cullen, and Matthew C. Weston. "Altered synaptic transmission and cortical architecture in a mouse model of Szt2 loss of function. " Central Virginia Society for Neuroscience, Blacksburg, Virginia
Aug 2022, Mona Safari, Carleigh Studtmann, Mackenzie A. Topolski, and Sharon A. Swanger. "Development of thalamic synapse alterations in a Dravet syndrome mouse model." VT Alliance for Neurodevelopment Research Symposium, Blacksburg, Virginia.
- Dr. Ray A. Gaskins Health Sciences Graduate Fellowship 2024–2025
- 1st Place Hokie Pitch Competition, Virginia Tech, 2021