Sex‐specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy

Abstract

Idiopathic generalized epilepsy represents about 30–35% of all epilepsies in humans. The bromodomain BRD2 gene has been repeatedly associated with the subsyndrome of juvenile myoclonic epilepsy. Our previous work determined that mice haploinsufficient in Brd2 (Brd2+/−) have increased susceptibility to provoked seizures, develop spontaneous seizures and have significantly decreased GABA markers in the direct basal ganglia pathway as well as in the neocortex and superior colliculus. Here we tested male and female Brd2+/− and wild type littermate mice in a battery of behavioral tests (open field, tube dominance test, elevated plus maze, Morris water maze and Barnes maze) to identify whether Brd2 haploinsufficiency is associated with the human behavioral patterns, so-called juvenile myoclonic epilepsy personality. Brd2+/− females but not males consistently displayed decreased anxiety. Further, we found a highly significant dominance trait (aggression) in the Brd2+/− mice compared to the wild type, more pronounced in females. Brd2+/− mice of either sex did not differ from wild type mice in spatial learning and memory tests. Compared to wild type littermates, we found decreased numbers GABA neurons in the basolateral amygdala, which is consistent with the increase in aggressive behavior. Our results indicate that Brd2+/− haploinsufficient mice show no cognitive impairment but have behavioral traits similar to those found in patients with juvenile myoclonic epilepsy (recklessness, aggression). This suggests that either the BRD2 gene is directly responsible for influencing many traits of juvenile myoclonic epilepsy or it controls upstream regulators of individual phenotypes.

Genetic Absence of nNOS Worsens Fetal Alcohol Effects in Mice. I: Behavioral Deficits

“…Activity levels, as reflected by the open field test, were not affected by sex [(although others have found that females are more active than males (Chachua et al, 2014)]. However, none of the behavioral results in this set of studies showed any significant main or interactive effects of sex.…”

Nonpsychotic Psychiatric Disorders in Juvenile Myoclonic Epilepsy

“…(31) T. Chachua et al (32) found a highly significant dominance trait (aggression) in Brd2+/-haploinsufficient mice compared with the wild type, more pronounced in females. Brd2+/-mice of either sex did not differ from wild-type mice in spatial learning and memory tests.…”

“…Brd2+/-haploinsufficient mice showed no cognitive impairment but had behavioral traits similar to those found in JME patients (recklessness, aggression. (9,32) It should be noted that Mendelian JME genes and nonMendelian risk alleles have not been detected in over 90% of affected patients. (33,34) In several patients with JME, AEDs contribute to the psychiatric manifestations; however, it does not mean that antiepileptic drugs need to be stopped.…”

Whatever happened to the primary generalized epilepsies of childhood and adolescence?

“…If we look back at what we know, the answer is yes. 10 Now that Lin et al 3 have provided such elegant data about the progression of the anatomical as well as cognitive abnormalities, one can go back to the putative animal models and see whether this finding can be replicated and its underlying pathological mechanisms studied in ways that are not feasible in the human. 8 More recently, JME has been linked with a mutation in BDR2 (RING3), which encodes a protein that is involved in regulating brain development.…”

“…9 Animal models with mutations in this gene show normal intelligence but subtle abnormalities in structure and behavior. 10 Now that Lin et al 3 have provided such elegant data about the progression of the anatomical as well as cognitive abnormalities, one can go back to the putative animal models and see whether this finding can be replicated and its underlying pathological mechanisms studied in ways that are not feasible in the human. These types of studies open up new avenues of both basic and clinical research that will hopefully lead to a much better understanding of the underlying disease and eventually to better treatment as well.…”