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Heterozygous GABAA receptor β3 subunit N110D knock‐in mice have epileptic spasms.

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Title: Heterozygous GABAA receptor β3 subunit N110D knock‐in mice have epileptic spasms.
Authors: Qu, Shimian (AUTHOR), Jackson, Laurel G. (AUTHOR), Zhou, Chengwen (AUTHOR), Shen, DingDing (AUTHOR), Shen, Wangzhen (AUTHOR), Nwosu, Gerald (AUTHOR), Howe, Rachel (AUTHOR), Catron, Mackenzie A. (AUTHOR), Flamm, Carson (AUTHOR), Biven, Marshall (AUTHOR), Kang, Jing‐Qiong (AUTHOR), Macdonald, Robert L. (AUTHOR)
Source: Epilepsia (Series 4). Apr2023, Vol. 64 Issue 4, p1061-1073. 13p.
Subjects: Thalamocortical system, Spasms, Lennox-Gastaut syndrome, Infantile spasms, Epilepsy, People with epilepsy, Pyramidal neurons, Somatosensory cortex
Abstract: Objective: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock‐in mouse with the human infantile spasms‐associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock‐in mouse as a model of infantile spasms syndrome. Methods: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock‐in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi‐unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. Results: The infantile spasms–associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock‐in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. Significance: The Gabrb3+/N110D knock‐in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Label: Title
  Group: Ti
  Data: Heterozygous GABA<subscript>A</subscript> receptor β3 subunit N110D knock‐in mice have epileptic spasms.
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  Data: <searchLink fieldCode="AR" term="%22Qu%2C+Shimian%22">Qu, Shimian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jackson%2C+Laurel+G%2E%22">Jackson, Laurel G.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhou%2C+Chengwen%22">Zhou, Chengwen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shen%2C+DingDing%22">Shen, DingDing</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Shen%2C+Wangzhen%22">Shen, Wangzhen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nwosu%2C+Gerald%22">Nwosu, Gerald</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Howe%2C+Rachel%22">Howe, Rachel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Catron%2C+Mackenzie+A%2E%22">Catron, Mackenzie A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Flamm%2C+Carson%22">Flamm, Carson</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Biven%2C+Marshall%22">Biven, Marshall</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kang%2C+Jing‐Qiong%22">Kang, Jing‐Qiong</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Macdonald%2C+Robert+L%2E%22">Macdonald, Robert L.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Apr2023, Vol. 64 Issue 4, p1061-1073. 13p.
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  Label: Subjects
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  Data: <searchLink fieldCode="DE" term="%22Thalamocortical+system%22">Thalamocortical system</searchLink><br /><searchLink fieldCode="DE" term="%22Spasms%22">Spasms</searchLink><br /><searchLink fieldCode="DE" term="%22Lennox-Gastaut+syndrome%22">Lennox-Gastaut syndrome</searchLink><br /><searchLink fieldCode="DE" term="%22Infantile+spasms%22">Infantile spasms</searchLink><br /><searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22People+with+epilepsy%22">People with epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Pyramidal+neurons%22">Pyramidal neurons</searchLink><br /><searchLink fieldCode="DE" term="%22Somatosensory+cortex%22">Somatosensory cortex</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock‐in mouse with the human infantile spasms‐associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock‐in mouse as a model of infantile spasms syndrome. Methods: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock‐in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi‐unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. Results: The infantile spasms–associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock‐in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. Significance: The Gabrb3+/N110D knock‐in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1111/epi.17470
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 13
        StartPage: 1061
    Subjects:
      – SubjectFull: Thalamocortical system
        Type: general
      – SubjectFull: Spasms
        Type: general
      – SubjectFull: Lennox-Gastaut syndrome
        Type: general
      – SubjectFull: Infantile spasms
        Type: general
      – SubjectFull: Epilepsy
        Type: general
      – SubjectFull: People with epilepsy
        Type: general
      – SubjectFull: Pyramidal neurons
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      – SubjectFull: Somatosensory cortex
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      – TitleFull: Heterozygous GABAA receptor β3 subunit N110D knock‐in mice have epileptic spasms.
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              Text: Apr2023
              Type: published
              Y: 2023
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