GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome
Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in <i>GABRB3</i> that encodes the GA...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8458 |
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| author | Gerald Ikemefuna Nwosu Wangzhen Shen Kirill Zavalin Sarah Poliquin Karishma Randhave Carson Flamm Marshall Biven Katherine Langer Jing-Qiong Kang |
| author_facet | Gerald Ikemefuna Nwosu Wangzhen Shen Kirill Zavalin Sarah Poliquin Karishma Randhave Carson Flamm Marshall Biven Katherine Langer Jing-Qiong Kang |
| author_sort | Gerald Ikemefuna Nwosu |
| collection | DOAJ |
| description | Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in <i>GABRB3</i> that encodes the GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) β<sub>3</sub> subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate <i>Gabrb3</i><sup>+/N328D</sup> knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing <i>Gabrb3</i> (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated <i>Gabrb3</i><sup>+/N328D</sup> mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and <i>Gabrb3</i><sup>+/N328D</sup> mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA<sub>A</sub>R subunit expression by Western blot. <i>Gabrb3</i><sup>+/N328D</sup> mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, <i>Gabrb3</i><sup>+/N328D</sup> mice showed reduced β<sub>3</sub> subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that <i>Gabrb3</i><sup>+/N328D</sup> mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:15:00Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-2e63c53717424f5297f6b37bfe03cfc22023-11-17T23:10:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249845810.3390/ijms24098458GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut SyndromeGerald Ikemefuna Nwosu0Wangzhen Shen1Kirill Zavalin2Sarah Poliquin3Karishma Randhave4Carson Flamm5Marshall Biven6Katherine Langer7Jing-Qiong Kang8Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USALennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in <i>GABRB3</i> that encodes the GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) β<sub>3</sub> subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate <i>Gabrb3</i><sup>+/N328D</sup> knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing <i>Gabrb3</i> (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated <i>Gabrb3</i><sup>+/N328D</sup> mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and <i>Gabrb3</i><sup>+/N328D</sup> mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA<sub>A</sub>R subunit expression by Western blot. <i>Gabrb3</i><sup>+/N328D</sup> mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, <i>Gabrb3</i><sup>+/N328D</sup> mice showed reduced β<sub>3</sub> subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that <i>Gabrb3</i><sup>+/N328D</sup> mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.https://www.mdpi.com/1422-0067/24/9/8458epilepsyknock-in mouse model<i>GABRB3</i>developmental epileptic encephalopathy |
| spellingShingle | Gerald Ikemefuna Nwosu Wangzhen Shen Kirill Zavalin Sarah Poliquin Karishma Randhave Carson Flamm Marshall Biven Katherine Langer Jing-Qiong Kang GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome International Journal of Molecular Sciences epilepsy knock-in mouse model <i>GABRB3</i> developmental epileptic encephalopathy |
| title | GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome |
| title_full | GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome |
| title_fullStr | GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome |
| title_full_unstemmed | GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome |
| title_short | GABA<sub>A</sub> Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome |
| title_sort | gaba sub a sub receptor β3 subunit mutation n328d heterozygous knock in mice have lennox gastaut syndrome |
| topic | epilepsy knock-in mouse model <i>GABRB3</i> developmental epileptic encephalopathy |
| url | https://www.mdpi.com/1422-0067/24/9/8458 |
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