Dataset Information

Functional characterization of a KCNAB3 genetic epilepsy with febrile seizures plus adult mouse model.

ABSTRACT:

Background

Genetic epilepsy with febrile seizures plus (GEFS+) is a type of epileptic syndrome closely related to heredity factors, which can be caused by gene mutations. However, it still remains unclear how these mutations result in seizures. Previously, we identified a new heterozygous missense mutation of the KCNAB3 gene, H258R, in the GEFS+ family; the electric currents of the human embryonic kidney 293 (HEK293) cells co-expressing Kvβ3 (H258R) and Kv1.1 showed obvious inactivation. This study sought to examine the effects of this mutation on the potassium channels in the mammalian brain.

Methods

Mutant mice were generated by introducing the human H258R missense mutation within exon 10 at an equivalent position in the mouse KCNAB3 gene via CRISPR/Cas9 and homologous recombination. A patch clamp was used to detect the potassium currents in the pyramidal cells of the hippocampal CA1 region of the mutant mice. The total potassium currents of the pyramidal cells in the hippocampal CA1 region of KCNAB3 [wild-type (WT)] and KCNAB3 (H258R) adult mice were recorded with increased voltage.

Results

We found a decreased total potassium current in the H258R group but no significant differences at a maximum voltage (+80 mV; P>0.05).

Conclusions

These results suggest that the KCNAB3 mutation reduced hippocampal potassium currents in this mouse model.

SUBMITTER: Ding J

PROVIDER: S-EPMC9636457 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Functional characterization of a <i>KCNAB3</i> genetic epilepsy with febrile seizures plus adult mouse model.

Ding Jian J Wang Chun C Huang Guo-Qiang GQ Zhang Jing-Wen JW Zhai Qiong-Xiang QX Chen Zhi-Hong ZH Zhang Yu-Xin YX Guo Yu-Xiong YX

Translational pediatrics 20221001 10

<h4>Background</h4>Genetic epilepsy with febrile seizures plus (GEFS+) is a type of epileptic syndrome closely related to heredity factors, which can be caused by gene mutations. However, it still remains unclear how these mutations result in seizures. Previously, we identified a new heterozygous missense mutation of the <i>KCNAB3</i> gene, H258R, in the GEFS+ family; the electric currents of the human embryonic kidney 293 (HEK293) cells co-expressing Kvβ3 (H258R) and Kv1.1 showed obvious inacti ...[more]

PMID: 36345448

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Project description:PurposeMutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations.MethodsUsing immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleep-wake pattern following 6 h of sleep deprivation.Key findingsImmunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation.SignificanceThese results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations.