Postsynaptic clustering of major GABA(A) 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 alpha and b eta subunits together with the gamma 2 subunit. Although the gamma 2 subuni t is not necessary for receptor assembly and translocation to the cell surf ace, we show here that it is required for clustering of major postsynaptic GABA(A) receptor subtypes. Loss of GABA(A) receptor clusters in mice defici ent in the gamma 2 subunit, and in cultured cortical neurons from these mic e, is paralleled by loss of the synaptic clustering molecule gephyrin and s ynaptic GABAergic function. Conversely, inhibiting gephyrin expression caus es loss of GABA(A) receptor clusters. The gamma 2 subunit and gephyrin are thus interdependent components of the same synaptic complex that is critica l for postsynaptic clustering of abundant subtypes of GABA(A) receptors in vivo.