Ubiquitin-dependent lysosomal targeting of GABA_A receptors regulates neuronal inhibition

The strength of synaptic inhibition depends partly on the number of GABA_A receptors (GABA_ARs) found at synaptic sites. The trafficking of GABA_ARs within the endocytic pathway is a key determinant of surface GABA_AR number and is altered in neuropathologies, such as cerebral ischemia. However, the molecular mechanisms and signaling pathways that regulate this trafficking are poorly understood. Here, we report the subunit specific lysosomal targeting of synaptic GABA _ARs. We demonstrate that the targeting of synaptic GABA_ARs into the degradation pathway is facilitated by ubiquitination of a motif within the intracellular domain of the γ2 subunit. Blockade of lysosomal activity or disruption of the trafficking of ubiquitinated cargo to lysosomes specifically increases the efficacy of synaptic inhibition without altering excitatory currents. Moreover, mutation of the ubiquitination site within the γ2 subunit retards the lysosomal targeting of GABA_ARs and is sufficient to block the loss of synaptic GABA_ARs after anoxic insult. Together, our results establish a previously unknown mechanism for influencing inhibitory transmission under normal and pathological conditions.