Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin

Most fast inhibitory neurotransmission in the brain is mediated by GABA_A receptors, which are mainly postsynaptic and consist of diverse α and β subunits together with the γ2 subunit. Although the γ2 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 γ2 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 γ2 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.