Rescue of γ2 subunit-deficient mice by transgenic overexpression of the GABAA receptor γ2S or γ2L subunit isoforms

The gamma 2 subunit is an important functional determinant of GABA(A) receptors and is essential for formation of high-affinity benzodiazepine binding sites and for synaptic clustering of major GABA(A) receptor subtypes along with gephyrin. There are two splice variants of the gamma 2 subunit, gamma 2 short (gamma 2S) and gamma 2 long (gamma 2L), the latter carrying in the cytoplasmic domain an additional eight amino acids with a putative phosphorylation site. Here, we show that transgenic mice expressing either the gamma 2S or gamma 2L subunit on a gamma 2 subunit-deficient background are phenotypically indistinguishable from wild-type. They express nearly normal levels of gamma 2 subunit protein and [H-3]flumazenil binding sites. Likewise, the distribution, number and size of GABA(A) receptor clusters colocalized with gephyrin are similar to wild-type in both juvenile and adult mice. Our results indicate that the two gamma 2 subunit splice variants can substitute for each other and fulfil the basic functions of GABA(A) receptors, allowing in vivo studies that address isoform-specific roles in phosphorylation-dependent regulatory mechanisms.