Loss of the Major GABA sub(A) Receptor Subtype in the Brain Is Not Lethal in Mice

The alpha 1 beta 2 gamma 2 is the most abundant subtype of the GABA sub(A) receptor 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 neurotransmission, we generated mice lacking either the alpha 1 or beta 2 subunit. In agreement with the reported abundance of this subtype, >50% of total GABA sub(A) receptors are lost in both alpha 1-/- and beta 2-/- mice. Surprisingly, homozygotes of both mouse lines are viable, fertile, and show no spontaneous seizures. Initially half of the alpha 1-/- mice died prenatally or perinatally, but they exhibited a lower mortality rate in subsequent generations, suggesting some phenotypic drift and adaptive changes. Both adult alpha 1-/- and beta 2-/- mice demonstrate normal performances on the rotarod, but beta 2-/- mice displayed increased locomotor activity. Purkinje cells of the cerebellum primarily express alpha 1 beta 2 gamma 2 receptors, and in electrophysiological recordings from alpha 1-/- mice GABA currents in these neurons are dramatically reduced, and residual currents have a benzodiazepine pharmacology characteristic of alpha 2- or alpha 3-containing receptors. In contrast, the cerebellar Purkinje neurons from beta 2-/- mice have only a relatively small reduction of GABA currents. In beta 2-/- mice expression levels of all six alpha subunits are reduced by similar to 50%, suggesting that the beta 2 subunit can coassemble with alpha subunits other than just alpha 1. Our data confirm that alpha 1 beta 2 gamma 2 is the major GABA sub(A) receptor subtype in the murine brain and demonstrate that, surprisingly, the loss of this receptor subtype is not lethal.