Presynaptic Terminals Independently Regulate Synaptic Clustering and Autophagy of GABAAReceptors inCaenorhabditis elegans

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Abstract
Synaptic clustering of GABAAreceptors 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 GABAAreceptor clustering during synaptogenesis, but the mechanisms of cluster formation and maintenance are not known. To study how presynaptic neurons direct the formation of GABAAreceptor clusters, we have investigated GABAAreceptor localization in postsynaptic cells that fail to receive presynaptic contacts inCaenorhabditis elegans. Postsynaptic muscles inC. elegansreceive acetylcholine and GABA motor innervation, and GABAAreceptors cluster opposite GABA terminals. Selective loss of GABA inputs caused GABAAreceptors to be diffusely distributed at or near the muscle cell surface, confirming that GABA presynaptic terminals induce GABAAreceptor clustering. In contrast, selective loss of acetylcholine innervation had no effect on GABAAreceptor localization. However, loss of both GABA and acetylcholine inputs together caused GABAAreceptors to traffic to intracellular autophagosomes. Autophagosomes normally transport bulk cytoplasm to the lysosome for degradation. However, we show that GABAAreceptors 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 GABAAreceptor clustering by independently controlling synaptic localization and surface stability of GABAAreceptors. They also demonstrate a novel function for autophagy in GABAAreceptor degradative trafficking.