Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor ?1 subunit.

ABSTRACT: Autosomal dominant mutations S326fs328X and A322D in the GABA(A) receptor ?1 subunit are associated with human absence epilepsy and juvenile myoclonic epilepsy, respectively. Because these mutations substantially reduce ?1 subunit protein expression in vitro, it was hypothesized that they produce epilepsy by causing ?1 subunit haploinsufficiency. However, in a mixed background strain of mice, ?1 subunit deletion does not reduce viability or cause visually apparent seizures; the effects of ?1 subunit deletion on electroencephalography (EEG) waveforms were not investigated. Here, we determined the effects of ?1 subunit loss on viability, EEG spike-wave discharges and seizures in congenic C57BL/6J and DBA/2J mice. Deletion of ?1 subunit caused strain- and sex-dependent reductions in viability. Heterozygous mice experienced EEG discharges and absence-like seizures within both background strains, and exhibited a sex-dependent effect on the discharges and viability in the C57BL/6J strain. These findings suggest that ?1 subunit haploinsufficiency can produce epilepsy and may be a major mechanism by which the S326fs328X and A322D mutations cause these epilepsy syndromes.

SUBMITTER: Arain FM 

PROVIDER: S-EPMC3418418 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature