Halff_2019_Cell.Rep_29_2599

GABAA receptors mediate fast inhibitory transmission in the brain, and their number can be rapidly up- or downregulated to alter synaptic strength. Neuroligin-2 plays a critical role in the stabilization of synaptic GABAA receptors and the development and maintenance of inhibitory synapses. To date, little is known about how the amount of neuroligin-2 at the synapse is regulated and whether neuroligin-2 trafficking affects inhibitory signaling. Here, we show that neuroligin-2, when internalized to endosomes, co-localizes with SNX27, a brain-enriched cargo-adaptor protein that facilitates membrane protein recycling. Direct interaction between the PDZ domain of SNX27 and PDZ-binding motif in neuroligin-2 enables membrane retrieval of neuroligin-2, thus enhancing synaptic neuroligin-2 clusters. Furthermore, SNX27 knockdown has the opposite effect. SNX27-mediated up- and downregulation of neuroligin-2 surface levels affects inhibitory synapse composition and signaling strength. Taken together, we show a role for SNX27-mediated recycling of neuroligin-2 in maintenance and signaling of the GABAergic synapse.