Cardiac arrhythmia in a mouse model of sodium channel
            <i>SCN8A</i>
            epileptic encephalopathy

Frasier, Chad R.; Wagnon, Jacy L.; Bao, Yang‐Yang; McVeigh, Luke; Lopez-Santiago, Luis F.; Meisler, Miriam H.; Isom, Lori L.

doi:10.1073/pnas.1612746113

Cited by 58 publications

(57 citation statements)

References 63 publications

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“…We propose that Scn8a N1768D/+ hippocampal CA1 and CA3 pyramidal neurons are hyperexcitable because of increased I Na,P conducted by mutant Na v 1.6 channels. We also propose that in CA1 pyramidal neurons, increased I Na,P results in localized increases in intracellular Na + to drive reverse mode Na/Ca exchange and alter intracellular Ca 2+ handling and the AP waveform, as we have proposed for Scn8a N1768D/+ cardiac myocytes (26).…”

Section: Discussionmentioning

confidence: 54%

“…EAD-like waveforms are rarely observed in central neurons, although they commonly occur in malfunctioning cardiac myocytes (32), where they have been implicated in the cardiac arrhythmogenic phenotype of a mouse model of Dravet syndrome (33). We showed increased incidence of a related AP waveform, delayed afterdepolarizations (DADs), in ventricular myocytes from Scn8a N1768D/+ mice (26). AP events with some similarity to our results, termed depolarizing afterpotentials (DAPs), have been observed in CA1 pyramidal neurons, but only in the presence of GABA receptor antagonists (34).…”

Section: Discussionmentioning

confidence: 86%

“…Reverse mode activity of the Na/Ca exchanger (NCX) contributes to the mechanism of hyperexcitability in Scn8a N1768D/+ cardiomyocytes (26). We used SN-6, a reverse mode NCX inhibitor (27), to test for a role for NCX in the EAD-like events observed in Scn8a N1768D/+ CA1 pyramidal cells.…”

Section: Scn8a N1768d/+ Ca1 Hippocampal Neurons In Acute Brain Slicesmentioning

confidence: 99%

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Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

Lopez-Santiago

Yuan

Wagnon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel gene SCN8A. Here, we investigated the neuronal phenotype of a mouse model expressing the gain-of-function SCN8A patient mutation, p.Asn1768Asp (Na v 1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons from Scn8a N1768D/+ mice showed increases in persistent sodium current (I Na ) density in CA1 pyramidal but not bipolar neurons. In CA3, I Na,P was increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing in Scn8a N1768D/+ pyramidal neurons in brain slices revealed early afterdepolarization (EAD)-like AP waveforms in CA1 but not in CA3 hippocampal or layer II/III neocortical neurons. The maximum spike frequency evoked by depolarizing current injections in Scn8a N1768D/+ CA1, but not CA3 or neocortical, pyramidal cells was significantly reduced compared with WT. Spontaneous firing was observed in subsets of neurons in CA1 and CA3, but not in the neocortex. The EAD-like waveforms of Scn8a N1768D/+ CA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistent I Na and reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate that Scn8a plays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13.sodium channel | epilepsy | mouse model | action potential | Na/Ca exchange

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 86%

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Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

Lopez-Santiago

Yuan

Wagnon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Clinical and animal studies demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized tonic-clonic seizures in many cases (Bateman et al, 2008; Blum, 2009; Bravo et al, 2015; Buchanan et al, 2014; Faingold et al, 2010; Langan et al, 2000; Pezzella et al, 2009; Ryvlin et al, 2013; So et al, 2000; Zhang et al, 2016), although cardiac dysfunction may also contribute to seizure-induced sudden death (Frasier et al, 2016; Kalume et al, 2013). Previous studies implicate serotonergic and adenosinergic neurotransmission in the pathogenesis of S-IRA in animal models of SUDEP, including the DBA/1 mouse (Feng and Faingold, 2015; Richerson et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

et al. 2017

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Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. The mechanisms of SUDEP are elusive, although cardiorespiratory dysfunction is a likely contributor. Clinical and animal studies indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death in many SUDEP cases. Our prior studies demonstrated that intraperitoneal (IP) injection of atomoxetine, a norepinephrine reuptake inhibitor (NRI) widely used to treat attention deficit hyperactivity disorder, suppresses S-IRA in DBA/1 mice. In the current study, we injected atomoxetine intracerebroventricularly (ICV) and measured its effect on S-IRA in DBA/1 mice to determine its central effects. Additionally, to test our hypothesis that atomoxetine reduces S-IRA via altering cardiorespiratory function, we examined the effect of atomoxetine on respiratory and cardiac function using non-invasive plethysmography and ECG in anesthetized DBA/1 mice, and on blood pressure and heart rate using a tail-cuff system in conscious DBA/1 mice. ICV administration of atomoxetine at 200–250 nmol significantly reduced S-IRA evoked by acoustic stimulation in DBA/1 mice, consistent with a central atomoxetine effect on S-IRA. Peripheral atomoxetine administration at a dosage that reduces S-IRA (15 mg/kg, IP) slightly increased basal ventilation and the ventilatory response to 7% CO2, but exerted no effect on heart rate in anesthetized DBA/1 mice. IP injection of atomoxetine produced no effect on the heart rate and blood pressures in conscious mice. These data suggest that atomoxetine suppresses S-IRA through direct effects on the CNS and potentially through enhanced lung ventilation in DBA/1 mice.

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“…Examples of syndromes necessitating referral or GC involvement included individuals with Marfan syndrome, Holt-Oram syndrome, Rett syndrome/MECP2 duplication, Andersen-Tawil syndrome, Danon disease, Williams syndrome, and Roberts syndrome. The GC also saw two patients with SCN8A-related disorder due to possible associations with cardiac arrhythmias (Frasier et al 2016). Twenty-nine encounters (10%) included patients with heritable congenital heart defects, primarily left-ventricular outflow tract obstructive defects and heterotaxy spectrum malformations.…”

Section: Resultsmentioning

confidence: 99%

The Genetic Counselor in the Pediatric Arrhythmia Clinic: Review and Assessment of Services

Helm

Freeze

Spoonamore

et al. 2017

Journal of Genetic Counseling

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There are minimal data on the impact of genetic counselors in subspecialty clinics, including the pediatric arrhythmia clinic. This study aimed to describe the clinical encounters of a genetic counselor integrated into a pediatric arrhythmia clinic. In the 20 months between July 2015 and February 2017, a total of 1914 scheduled patients were screened for indications relevant for assessment by a genetic counselor. Of these, the genetic counselor completed 276 patient encounters, seeing 14.4% of all patients in clinic. The most expected and common indications for genetic counselor involvement were related to suspicion for primary heritable arrhythmia conditions, though patients seen in this clinic display a wide range of cardiac problems and many additional indications for genetic evaluation were identified. Roughly 75% (211/276) of encounters were for personal history of confirmed/suspected heritable disease, including cardiac channelopathies, cardiomyopathies, ventricular arrhythmias, and congenital heart defects, and 25% (65/276) were for family history of disease, including long QT syndrome and sudden unexplained death. Overall, this study shows that about 1 in 7 patients seen in a pediatric arrhythmia clinic have indications that likely benefit from genetic counselor involvement and care. Similar service delivery models embedding genetic counselors in pediatric arrhythmia clinics should be encouraged, and this model could be emulated to increase patient access to genetic counseling services.

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Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

Cited by 58 publications

References 63 publications

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

The Genetic Counselor in the Pediatric Arrhythmia Clinic: Review and Assessment of Services

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