Modulation of GABA A receptor trafficking by WWC2 reveals class-specific mechanisms of synapse regulation by WWC family proteins.

WWC2 (WW and C2 domain-containing protein) is implicated in several neurological disorders, however its function in the brain has yet to be determined. Here, we demonstrate that WWC2 interacts with inhibitory but not excitatory postsynaptic scaffolds, consistent with prior proteomic identification of WWC2 as a putative component of the inhibitory postsynaptic density. Using mice lacking WWC2 expression in excitatory forebrain neurons, we show that WWC2 suppresses GABA A R incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABA A R recycling to the membrane. Inhibitory synaptic transmission is dysregulated in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (WWC1), a key regulator of AMPA receptor trafficking at excitatory synapses, deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABA A R membrane expression. These data reveal unique, synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABA A R membrane expression.