Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin

Most fast inhibitory neurotransmission in the brain is mediated by GABA(A) receptors, which are mainly postsynaptic and consist of diverse alpha and beta subunits together with the gamma 2 subunit. Although the gamma 2 subunit is not necessary for receptor assembly and translocation to the cell surface, we show here that it is required for clustering of major postsynaptic GABA(A) receptor subtypes. Loss of GABA(A) receptor clusters in mice deficient in the gamma 2 subunit, and in cultured cortical neurons from these mice, is paralleled by loss of the synaptic clustering molecule gephyrin and synaptic GABAergic function. Conversely, inhibiting gephyrin expression causes loss of GABA(A) receptor clusters. The gamma 2 subunit and gephyrin are thus interdependent components of the same synaptic complex that is critical for postsynaptic clustering of abundant subtypes of GABA(A) receptors in vivo.