Development of Pathologic Neural Networks and Seizures in a Pediatric Mouse Model of KCNQ3 Gain-of-function Epilepsy
Abstract number :
3.028
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2022
Submission ID :
2204161
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Liang Ma, MS – Columbia University; Divyalakshmi Soundararajan, MS – Staff Associate, Institute for Genomic Medicine, Columbia University; Wayne Frankel, PhD – Director of Preclinical Disease Models, Institute for Genomic Medicine, Columbia University; Tristan Sands, MD, PhD – Assistant Professor in Neurology, Institute for Genomic Medicine, Columbia University; Jennifier Gelinas, MD, PhD – Assistant Professor in Neurology, Institute for Genomic Medicine, Columbia University
Rationale: KCNQ3 gain-of-function (GoF) mutations result in abundant sleep-activated epileptic discharges and autistic features in affected pediatric patients. How and when this epileptic activity emerges during brain development, and its effect on physiologic network function is unknown. Using large-scale, high spatiotemporal resolution in vivo electrophysiology, we aimed to address these questions in a mouse model harboring a R231H mutation in Kcnq3 (C57BL/6J), orthologous to the human pathogenic R230H gain-of-function variant.
Methods: We performed acute intracranial EEG recordings in wild type and heterozygous mutant mouse pups, at the end of the first postnatal week (P6-7) and the end of the second postnatal week (P13-P14), corresponding to the human pediatric age range. We used a type of dense, thin, flexible, and conformable electrode arrays to cover a large portion of dorsal cortical surface and record simultaneously from multiple cortical regions during normal sleep/wake cycles. Electrode positions were confirmed immunohistochemically postmortem in flattened brain slices.
Results: We found that physiologic activity patterns were deranged in KCNQ3 GoF mutant pups as early as the first week of life, with evidence of abnormal temporal and spatial synchronization relative to wildtype pups. Frank focal interictal epileptiform discharges emerged by the second postnatal week, along with prolonged epochs of continuous epileptic activity. Moreover, network activity during interictal periods of these mutant pups was immature compared to expected developmental patterns.
Conclusions: We have identified early markers of network dysregulation in KCNQ3 GoF mutant mice, and evidence for abnormal network maturation in addition to emergence of epileptic activity. Abnormal early network activity during this critical window of neurodevelopment might indicate and/or contribute to neuropsychiatric symptoms. These studies could help identify novel targets for therapeutics and timely windows for treatment.
Funding: National Institutes of Health (R21 EY032381)
Basic Mechanisms