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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.

GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy