Presynaptic Terminals Independently Regulate Synaptic Clustering and Autophagy of GABA sub(A) Receptors in Caenorhabditis elegans

Synaptic clustering of GABA sub(A) receptors is important for the function of inhibitory synapses, influencing synapse strength and, consequently, the balance of excitation and inhibition in the brain. Presynaptic terminals are known to induce GABA sub(A) receptor clustering during synaptogenesis, but the mechanisms of cluster formation and maintenance are not known. To study how presynaptic neurons direct the formation of GABA sub(A) receptor clusters, we have investigated GABA sub(A) receptor localization in postsynaptic cells that fail to receive presynaptic contacts in Caenorhabditis elegans. Postsynaptic muscles in C. elegans receive acetylcholine and GABA motor innervation, and GABA sub(A) receptors cluster opposite GABA terminals. Selective loss of GABA inputs caused GABA sub(A) receptors to be diffusely distributed at or near the muscle cell surface, confirming that GABA presynaptic terminals induce GABA sub(A) receptor clustering. In contrast, selective loss of acetylcholine innervation had no effect on GABA sub(A) receptor localization. However, loss of both GABA and acetylcholine inputs together caused GABA sub(A) receptors to traffic to intracellular autophagosomes. Autophagosomes normally transport bulk cytoplasm to the lysosome for degradation. However, we show that GABA sub(A) receptors traffic to autophagosomes after endocytic removal from the cell surface and that acetylcholine receptors in the same cells do not traffic to autophagosomes. Thus, autophagy can degrade cell-surface receptors and can do so selectively. Our results show that presynaptic terminals induce GABA sub(A) receptor clustering by independently controlling synaptic localization and surface stability of GABA sub(A) receptors. They also demonstrate a novel function for autophagy in GABA sub(A) receptor degradative trafficking.