title: GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy.
abstract: 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.
authors: Department of Cell Biology & Anatomy, New York College of Medicine, Valhalla, New York, United States of America. libor_velisek@nymc.edu
authors: Libor
authors: L
authors: Velíšek
authors: Enyuan
authors: E
authors: Shang
authors: Jana
authors: J
authors: Velíšková
authors: Tamar
authors: T
authors: Chachua
authors: Stephania
authors: S
authors: Macchiarulo
authors: Giorgi
authors: G
authors: Maglakelidze
authors: Debra J
authors: DJ
authors: Wolgemuth
authors: David A
authors: DA
authors: Greenberg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone; D004198:Disease Susceptibility; D004569:Electroencephalography; D004829:Epilepsy, Generalized / Q000473:pathology*; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology*; D057895:Haploinsufficiency / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
chemical_list: D015415:Biomarkers; D002868:Chromosomal Proteins, Non-Histone; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins