Scn2a deletion improves survival and brain–heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP)

Mishra, Vikas; Karumuri, Bharat K.; Gautier, Nicole; Liu, Rui; Hutson, T. Noah; Vanhoof-Villalba, Stephanie L.; Vlachos, Ioannis; Iasemidis, Leonidas D.; Glasscock, Edward

doi:10.1093/hmg/ddx104

Cited by 49 publications

(54 citation statements)

References 67 publications

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“…2A, C), similar to previous reports. 4 However, VEH-injected Kcnq1 A340E/A340E mice showed latencies that were not significantly different from their C57BL/6 WT counterparts (Fig. 2B, D), indicating the Kcnq1 A340E mutation does not affect seizure threshold despite the occurrence of infrequent spontaneous seizures in this model.…”

Section: Resultsmentioning

confidence: 79%

“…However, baseline RMSSD was nearly twice as high in Kcna1 −/− mice compared to their Tac:N:NIHS-BC WT controls, consistent with a previous study showing elevated HRV measures of parasympathetic tone in these animals. 4 Upon 10 mg·kg −1 RTG administration, SDNN (t = 3.488, P = 0.025, paired t-test) and RMSSD (t = 3.373, P = 0.028, paired t-test) significantly increased by 4-fold and 8-fold, respectively, in Kcnq1 A340E/A340E mice compared to VEH (Table 1), suggesting dysregulation of autonomic control of the heart in response to the drug. In contrast, Kcna1 −/− mice showed no change in HRV following RTG injection (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…4 Avertin was prepared by mixing 250 mg 2,2,2-tribromoethanol (Sigma-Aldrich, St. Louis, MO) with 155 μL 2-methyl-2-butanol (Sigma-Aldrich, St. Louis, MO) dissolved in 19.75 mL double-distilled water heated to 40°C, followed by filter-sterilization prior to use. Simultaneous video and cortical EEG-ECG activity were recorded in freely moving mice using a digital video EEG-ECG monitoring system (Data Sciences International; St. Paul, MN).…”

Section: Methodsmentioning

confidence: 99%

“…HRV was measured in the time domain using the standard deviation of the RR intervals (SDNN) and the root mean square of successive differences (RMSSD) as done previously. 4 All cardiac parameters were measured during the light phase of the day between 10:30 a.m. and 4:30 p.m.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy

et al. 2017

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This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy

et al. 2017

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“…Previously Glasscock et al reported bradycardia events and increased HRV in KO mice on a Tac:N:NIHS‐BC background age 1‐3 months . On this strain background 60% die by P70, but it is unclear whether all KO mice have early mortality . Here, we used KO mice on the C3H/FeJ background, which have 100% mortality by P78 (Figure A) .…”

Section: Resultsmentioning

confidence: 99%

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

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Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

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Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic‐like behaviors due to Scn2a haploinsufficiency

et al. 2021

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Background Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Previous studies have shown that Scn2a+/– ameliorates epilepsy in Kcna1–/– mice, improving survival, seizure characteristics, and brain–heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD‐like repetitive and social behaviors in Scn2a+/– mice. Methods Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. Results Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1–/– mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1+/–) exhibited increased self‐grooming and decreased sociability suggestive of ASD‐like features similar to those observed in Scn2a+/– mice. In double‐mutant Scn2a+/–; Kcna1+/– mice, the two mutations interacted to partially normalize ASD‐like behaviors associated with each mutation independently. Conclusions Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD.

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Scn2a deletion improves survival and brain–heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP)

Cited by 49 publications

References 67 publications

Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy

Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic‐like behaviors due to Scn2a haploinsufficiency

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