WWC2 modulates GABAA-receptor-mediated synaptic transmission, revealing class-specific mechanisms of synapse regulation by WWC family proteins

• Published in: Cell reports (Cambridge) Vol. 43; no. 10; p. 114841
• Main Authors: Dunham, Thomas L., Wilkerson, Julia R., Johnson, Richard C., Huganir, Richard L., Volk, Lenora J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 22-10-2024
• Subjects: AMPA receptor; dendritic arborization; GABAA receptor; GRIP1; HAP1; inhibitory synapse; KIBRA; synaptic transmission; WWC1; WWC2; KIBRA; GRIP1; AMPA receptor; CP: Neuroscience; WWC1; WWC2; synaptic transmission; HAP1; GABAA receptor; inhibitory synapse; dendritic arborization
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114841

The WW and C2 domain-containing protein (WWC2) is implicated in several neurological disorders. 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 γ-aminobutyric acid type-A receptor (GABAAR) incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABAAR recycling to the membrane. Inhibitory synaptic transmission is increased in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (kidney/brain protein; WWC1), a key regulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking at excitatory synapses, the deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABAAR membrane expression. These data reveal synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABAAR membrane expression.
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•WWC2 KO results in increased surface GABAAR expression and fIPSP amplitude•WWC2 interacts with the GABAAR recycling proteins GRIP1 and HAP1•WWC2 KO neurons have dendritic branching deficits•WWC2 and KIBRA exhibit selective regulation of GABAARs and AMPARs, respectively
WWC gene (Wwc1–3) expression has been implicated in several brain disorders. Dunham et al. show that WWC2 regulates GABAA receptor surface expression and inhibitory synaptic function in the hippocampus. They identify divergent synaptic functions for WWC2 compared to WWC1 (KIBRA), a regulator of AMPAR trafficking and excitatory synaptic plasticity.