Rescue of gamma 2 subunit-deficient mice by transgenic overexpression of the GABA(A) receptor gamma 2S or gamma 2L subunit isoforms

The gamma 2 subunit is an important functional determinant of GABA(A) recep tors 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 phospho rylation site. Here, we show that transgenic mice expressing either the gam ma 2S or gamma 2L subunit on a gamma 2 subunit-deficient background are phe notypically indistinguishable from wild-type. They express nearly normal le vels of gamma 2 subunit protein and [H-3]flumazenil binding sites. Likewise , the distribution, number and size of GABA(A) receptor clusters colocalize d with gephyrin are similar to wild-type in both juvenile and adult mice. O ur results indicate that the two gamma 2 subunit splice variants can substi tute for each other and fulfil the basic functions of GABA(A) receptors, al lowing in vivo studies that address isoform-specific roles in phosphorylati on-dependent regulatory mechanisms.