Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783536593572724736 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7238755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT qushimian gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT catronmackenzie gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT zhouchengwen gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT janvevaishali gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT shenwangzhen gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT howerachelk gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice AT macdonaldrobertl gabaareceptorb3subunitmutationd120ncauseslennoxgastautsyndromeinknockinmice |