Abstracts

Rationale: Heterozygous loss-of-function mutations of the GABAA receptor alpha 1 subunit (GABRA1) are associated with two human autosomal dominant idiopathic generalized epilepsy syndromes. However, previous studies suggested that when expressed in a mixed background mouse strain, homozygous and heterozygous GABRA1 knockout mutations did not affect viability or cause spontaneous, visually apparent seizures. Here, we determined the effects of GABRA1 knockout mutations on viability and electrographic epileptiform activity in mice maintained in C57Bl/6 and DBA congenic lines Methods: We obtained heterozygous GABRA1 knockout mice in a congenic C57BL/6 background strain and also bred them into a congenic DBA/2J stain. We monitored these animals for their rate of weight gain in their post-weaning period and their mortality rate. We also performed continuous EEG recordings on wild type and heterozygous knockout mice between the ages of postnatal day (P) 30-35 to evaluate for the presence of any epileptiform abnormalities as well as their response to the antiepileptic drug, ethosuximide.Results: In contrast to what was found in mixed-background mice, we observed that the GABRA1 knockout mutation increased mortality in a gene dose-dependent manner in congenic C57BL/6 mice with most of the increased deaths beginning shortly after weaning. Although heterozygous and homozygous GABRA1 knockout did not significantly increase mortality in DBA/2J mice, it did significantly reduce post-weaning gains in body mass in DBA/2J females. We also discovered that the heterozygous GABRA1 knockout mutation caused bilaterally synchronous 7-8 Hz epileptiform EEG spike discharges (SD) in both C57BL/6 mice (12 3 SD/ hr) and DBA/2J mice (8 3 SD/hr). The duration of these discharges were short and lasted an average of only 1.2 0.07 seconds in C57BL/6 mice and 1.8 0.2 seconds in DBA/2J mice. The antiepileptic drug, ethosuximide reduced the incidence of SD.Conclusions: The finding that these mice possessed spontaneous epileptiform activity suggests that the heterozygous ?1 subunit loss-of-function caused by the human epilepsy-associated GABRA1 mutations substantially contributes to the epilepsy phenotype. In addition, our data demonstrates that genetic background strongly influences the expression of the disease.