Identification of Sodium Channel Dysfunction in Chromosome 15q11.2-13.1 Duplication Syndrome, a Genetic Form of Epilepsy and Autism
Abstract number :
1.437
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2022
Submission ID :
2232933
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Marwa Elamin, MBBS, PhD – University of Connecticut Health Center; Fouad Lemtiri-Chlieh, Ph.D. – Neuroscience – University of Connecticut School of medicine; Tiwanna Robinson, M.A. – Neuroscience – University of Connecticut School of medicine; Deepa Anjan Kumar, M.S. – Neuroscience – University of Connecticut School of medicine; Stormy Chamberlain, Ph.D. – University of Connecticut School of medicine; Eric Levine, Ph.D. – Neuroscience – University of Connecticut School of medicine
This is a Late Breaking abstract
Rationale: Maternal duplication of the chromosome 15q11-q13.1 region causes Dup15q syndrome, a highly penetrant neurodevelopmental disorder characterized by severe autism and refractory seizures. Although UBE3A, the gene encoding the ubiquitin protein ligase E3A, is thought to be the main driver of the disease phenotypes, the exact cellular and molecular mechanisms that contribute to the development of the syndrome are yet to be determined.
Methods: In this study, we reprogrammed fibroblasts from an individual affected by Dup15q syndrome to generate an induced pluripotent stem cell (iPSC) line. We then employed a novel CRISPR-based technique to remove the extra isodicentric chromosome and create an isogenic control line. Using whole-cell patch clamp electrophysiology, we compared Dup15q neurons to their isogenic corrected counterparts, and we uncovered multiple hyperexcitability phenotypes including increased action potential firing frequency and an increased inward current density, which prompted us to further investigate sodium channel kinetics.
Results: Compared to the corrected neurons, voltage-gated sodium currents in Dup15q neurons show a depolarizing shift in the fast inactivation curve, a longer time for slow inactivation to take effect, and faster recovery from both inactivation types. A fraction of Dup15q neurons (~ 15 -20%) appears to be resistant to slow inactivation of the sodium current. Not unexpectedly, a higher fraction of persistent sodium current is also observed in Dup15q neurons.
Conclusions: Sodium channels play a crucial role in the generation of action potentials, and sodium channelopathies have been uncovered in multiple forms of epilepsy. For the first time, our work identifies an early sodium channel dysfunction in human Dup15q syndrome neurons. Specifically, we uncovered deficits in inactivation kinetics and an increase in persistent current, which have been previously linked to multiple forms of epilepsy and can potentially underly the hyperexcitability phenotypes observed in this genetic form of epilepsy and autism.
Funding: NIH Grants NS111965 and NS111986, The Eagles Autism Foundation, Schlumberger Foundation
Basic Mechanisms