A5049435505- Neuroscience and Neuropharmacology Research
- Epilepsy research and treatment
- Neonatal and fetal brain pathology
- Ion channel regulation and function
- Genetics and Neurodevelopmental Disorders
- Neural dynamics and brain function
- Neuroscience of respiration and sleep
- Neonatal Respiratory Health Research
- Sleep and Wakefulness Research
- Algal biology and biofuel production
- Anesthesia and Neurotoxicity Research
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- EEG and Brain-Computer Interfaces
- RNA Research and Splicing
- Memory and Neural Mechanisms
- Microbial Community Ecology and Physiology
- Hippo pathway signaling and YAP/TAZ
- Neurogenesis and neuroplasticity mechanisms
- Genomic variations and chromosomal abnormalities
- Neonatal and Maternal Infections
- Neurogenetic and Muscular Disorders Research
- Cardiac electrophysiology and arrhythmias
- Cellular transport and secretion
- Photoreceptor and optogenetics research
University of Virginia
2018-2024
University of Virginia Health System
2021-2023
De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk sudden death. p.Arg1872Trp is a recurrent de mutation reported 14 unrelated individuals that included seizure onset prenatal or infantile period severe verbal ambulatory comorbidities. The major biophysical effect was previously shown to be impaired inactivation accompanied by increased current density. We have generated conditional mouse...
Objective Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of that believed to be due cardiorespiratory failure immediately after generalized convulsive seizures. Methods We performed monitoring seizure‐induced mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation single Scn8a allele—mutations identified from patients who died SUDEP—and pentylenetetrazole‐treated wild‐type mice. Results The primary cause for all was apnea, as (1) apnea began...
SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant , which encodes the voltage-gated sodium channel Na V 1.6. To date, it unclear if and how inhibitory interneurons, express 1.6, influence disease pathology. Using both sexes of transgenic mouse model encephalopathy, we found that selective expression R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility audiogenic seizures. Patch-clamp electrophysiology experiments revealed...
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of amongst patients whose seizures are not adequately controlled by current therapies. Patients with SCN8A encephalopathy have an elevated risk for SUDEP. While transgenic mouse models provided insight into molecular mechanisms etiology, our understanding seizure-induced has been hampered inability to reliably trigger both and these mice. Here, we demonstrate that mice harboring Scn8a allele patient-derived mutation N1768D...
Objective To identify circuits active during neonatal hypoxic–ischemic (HI) seizures and seizure propagation using electroencephalography (EEG), behavior, whole‐brain neuronal activity mapping. Methods Mice were exposed to HI on postnatal day 10 unilateral carotid ligation global hypoxia. EEG video recorded for the duration of experiment. Using immediate early gene reporter mice, cells expressing cfos permanently tagged with protein tdTomato a 90‐minute window. After 1 week, allowing maximal...
Kainate receptors (KARs) are glutamate with peak expression during late embryonic and early postnatal periods. Altered KAR-mediated neurotransmission subunit observed in several brain disorders, including epilepsy. Here, we examined the role of KARs regulating seizures neonatal C57BL/6 mice exposed to a hypoxic insult. We found that knockout GluK2 subunit, or blockade by UBP310 reduced seizure susceptibility period reoxygenation. Following insult, an increase excitatory hippocampal CA3...
SCN8A epileptic encephalopathy is caused predominantly by de novo gain-of-function mutations in the voltage-gated sodium channel Na
Objective To examine acute seizure activity and neuronal damage in a neonatal mouse model of inflammation-sensitized hypoxic-ischemic (IS-HI) brain injury utilizing continuous electroencephalography (cEEG) neurohistology. Methods Neonatal mice were exposed to either IS-HI with Escherichia coli lipopolysaccharide (LPS) or HI alone on postnatal (p) day 10 using unilateral carotid artery ligation followed by global hypoxia (n = [5 female, 5 male] for IS-HI, n 12 7 alone). Video cEEG was...
Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8-17% patients with epilepsy. Although mechanisms SUDEP are unknown, one proposed mechanism is abnormal control heart by autonomic nervous system (ANS). Our objective was to determine whether broad changes ictal rate experienced mouse models (1) due ANS and (2) contribute seizure-induced death. Seizures were induced electrical stimulation hippocampus a carrying human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D;...
Hypoxia ischemia is the most common cause of neonatal seizures. Animal models are crucial for understanding mechanisms and physiology underlying seizures hypoxia ischemia. This manuscript describes a method continuous video electroencephalogram (EEG) monitoring in mice to detect analyze EEG background during Use conjunction allows description seizure semiology confirmation also analysis power spectrograms pattern trends over experimental time period. In this model, recording prior injury...
Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there limited options treating curing the other conditions, is not an option all cases pharmacoresistant epilepsy. Understanding genetic neurobiological mechanisms underlying MCD necessary step elucidating novel therapeutic...
Hypoxia ischemia is the most common cause of neonatal seizures. Animal models are crucial for understanding mechanisms and physiology underlying seizures hypoxia ischemia. This manuscript describes a method continuous video electroencephalogram (EEG) monitoring in mice to detect analyze EEG background during Use conjunction allows description seizure semiology confirmation also analysis power spectrograms pattern trends over experimental time period. In this model, recording prior injury...
<h3>Objective:</h3> We previously showed PRAX-562 inhibits persistent sodium current (I<sub>Na</sub>) with preference over peak I<sub>Na</sub> compared to standard-of-care. This profile was efficacious in two DEE mouse models gain-of-function (GoF) mutations voltage-gated channels (Na<sub>V</sub>). Here we investigated the anticonvulsant activity of non-Na<sub>V</sub> models: <i>Kcnq2</i><sup>K556E/+</sup>and <i>Kcnc1</i><sup>R320H/+</sup>. <h3>Background:</h3> Persistent I<sub>Na</sub>, a...
Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected and unexplained death of a person with epilepsy accounts for between 8 17% epilepsy-related deaths, rising to 50% patients refractory epilepsy. In mouse model SUDEP, we have recently shown that due seizure-induced respiratory arrest. addition, apnea initiated during tonic phase muscle contraction possible mechanism apnea. present study, explore 1) whether activity inspiratory rhythm generator brainstem and/or 2)...
Abstract SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant which encodes the voltage-gated sodium channel Na V 1.6. To date, it unclear if and how inhibitory interneurons, express 1.6, influence disease pathology. We found that selective expression of R1872W mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility audiogenic seizures. SST from mice were hyperexcitable but hypersensitive action potential failure via depolarization...