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.

Thalamic volume reduction in drug‐naive patients with new‐onset genetic generalized epilepsy

“…However, the pathophysiologic mechanisms explaining the relationship between GGE and thalamic volume loss are still unknown. One possible mechanism might relate to genetic variation in bromodomain containing 2, reported in JME patients39 which has been found to lead to γ‐aminobutyric acid (GABA)ergic neuron deficit found in mice40; this might associate with thalamic volume loss as reported here.…”

A Review of the Differences in Developmental, Psychiatric, and Medical Endophenotypes Between Males and Females with Autism Spectrum Disorder

“…Previous research on epilepsy suggests that females experience more idiopathic generalized epilepsy (IGE) than males (Camfield et al, 2013; Camfield and Camfield, 2009; Valentin et al, 2007). IGE is familial related and some genetic causes of IGE are known (e.g., mutations on the sodium channel and GABA receptors) (Velisek et al, 2011; Amiet et al, 2008). It has been suggested that some of these same genetic causes of epilepsy – particular those that implicate genetic mutations on sodium channels –may represent ASD phenocopies that deserve further exploration (Amiet et al, 2008).…”

The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

“…Heterozygous Brd2 +/− mice are viable and overtly normal, but have a decreased tonic-clonic seizure threshold compared to Brd2 +/+ wild type mice. Further, anatomical analysis of the brain shows that the number of GABAergic neurons in the neocortex and the striatum of Brd2 +/− mice are decreased, compared to those in Brd2 +/+ mice [52]. These findings indicate that an insufficiency of BRD2 protein is associated with a decrease in the number of neuronal cells required for critical brain structures.…”