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GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice

The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified...

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Autores principales: Qu, Shimian, Catron, Mackenzie, Zhou, Chengwen, Janve, Vaishali, Shen, Wangzhen, Howe, Rachel K, Macdonald, Robert L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238755/
https://www.ncbi.nlm.nih.gov/pubmed/32467926
http://dx.doi.org/10.1093/braincomms/fcaa028
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author Qu, Shimian
Catron, Mackenzie
Zhou, Chengwen
Janve, Vaishali
Shen, Wangzhen
Howe, Rachel K
Macdonald, Robert L
author_facet Qu, Shimian
Catron, Mackenzie
Zhou, Chengwen
Janve, Vaishali
Shen, Wangzhen
Howe, Rachel K
Macdonald, Robert L
author_sort Qu, Shimian
collection PubMed
description The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox–Gastaut syndrome. To determine whether the mutation causes Lennox–Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3(+/D120N) knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic–clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox–Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3(+/D120N) knock-in mouse recapitulated human Lennox–Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox–Gastaut syndrome development and for the development of new antiepileptic drugs and treatments.
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spelling pubmed-72387552020-05-26 GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice Qu, Shimian Catron, Mackenzie Zhou, Chengwen Janve, Vaishali Shen, Wangzhen Howe, Rachel K Macdonald, Robert L Brain Commun Original Article The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox–Gastaut syndrome. To determine whether the mutation causes Lennox–Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3(+/D120N) knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic–clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox–Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3(+/D120N) knock-in mouse recapitulated human Lennox–Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox–Gastaut syndrome development and for the development of new antiepileptic drugs and treatments. Oxford University Press 2020-03-10 /pmc/articles/PMC7238755/ /pubmed/32467926 http://dx.doi.org/10.1093/braincomms/fcaa028 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Qu, Shimian
Catron, Mackenzie
Zhou, Chengwen
Janve, Vaishali
Shen, Wangzhen
Howe, Rachel K
Macdonald, Robert L
GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title_full GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title_fullStr GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title_full_unstemmed GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title_short GABA(A) receptor β3 subunit mutation D120N causes Lennox–Gastaut syndrome in knock-in mice
title_sort gaba(a) receptor β3 subunit mutation d120n causes lennox–gastaut syndrome in knock-in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238755/
https://www.ncbi.nlm.nih.gov/pubmed/32467926
http://dx.doi.org/10.1093/braincomms/fcaa028
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