Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice

The alpha1 beta2 gamma2 is the most abundant subtype of the GABA(A) recepto r and is localized in many regions of the brain. To gain more insight into the role of this receptor subtype in the modulation of inhibitory neurotran smission, we generated mice lacking either the alpha1 or beta2 subunit. In agreement with the reported abundance of this subtype,.50% of total GABA(A) receptors are lost in both alpha1/-/- and 2 mice. Surprisingly, homozygote s of both mouse lines are viable, fertile, and show no spontaneous seizures . Initially half of the alpha1-2/- 2 mice died prenatally or perinatally, b ut they exhibited a lower mortality rate in subsequent generations, suggest ing some phenotypic drift and adaptive changes. Both adult alpha1-/- and be ta2-/- mice demonstrate normal performances on the rotarod, but beta2-/- mi ce displayed increased locomotor activity. Purkinje cells of the cerebellum primarily express alpha1 beta2 gamma2 receptors, and in electrophysiologic al recordings from alpha1-/- mice GABA currents in these neurons are dramat ically reduced, and residual currents have a benzodiazepine pharmacology ch aracteristic of alpha2- or alpha3- containing receptors. In contrast, the c erebellar Purkinje neurons from beta2-/- mice have only a relatively small reduction of GABA currents. In beta2-/- mice expression levels of all six a subunits are reduced by similar to 50%, suggesting that the beta2 subunit can coassemble with a subunits other than just alpha1. Our data confirm tha t alpha1 beta2 gamma2 is the major GABA(A) receptor subtype in the murine b rain and demonstrate that, surprisingly, the loss of this receptor subtype is not lethal.