GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mi...

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Autores principales:	Libor Velíšek, Enyuan Shang, Jana Velíšková, Tamar Chachua, Stephania Macchiarulo, Giorgi Maglakelidze, Debra J Wolgemuth, David A Greenberg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b35688e638374321aa40bddf05b34973
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spelling	oai:doaj.org-article:b35688e638374321aa40bddf05b349732021-11-18T06:47:22ZGABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.1932-620310.1371/journal.pone.0023656https://doaj.org/article/b35688e638374321aa40bddf05b349732011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21887291/?tool=EBIhttps://doaj.org/toc/1932-6203Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.Libor VelíšekEnyuan ShangJana VelíškováTamar ChachuaStephania MacchiaruloGiorgi MaglakelidzeDebra J WolgemuthDavid A GreenbergPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23656 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Libor Velíšek Enyuan Shang Jana Velíšková Tamar Chachua Stephania Macchiarulo Giorgi Maglakelidze Debra J Wolgemuth David A Greenberg GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
description	Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.
format	article
author	Libor Velíšek Enyuan Shang Jana Velíšková Tamar Chachua Stephania Macchiarulo Giorgi Maglakelidze Debra J Wolgemuth David A Greenberg
author_facet	Libor Velíšek Enyuan Shang Jana Velíšková Tamar Chachua Stephania Macchiarulo Giorgi Maglakelidze Debra J Wolgemuth David A Greenberg
author_sort	Libor Velíšek
title	GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
title_short	GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
title_full	GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
title_fullStr	GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
title_full_unstemmed	GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
title_sort	gabaergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of brd2 haploinsufficiency in juvenile myoclonic epilepsy.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/b35688e638374321aa40bddf05b34973
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GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.

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