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标题：Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors
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作者：Wei Chou Tseng ; Paul M. Jenkins ; Masashi Tanaka 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：4
页码：1214-1219
DOI：10.1073/pnas.1417989112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGABAA-receptor-based interneuron circuitry is essential for higher order function of the human nervous system and is implicated in schizophrenia, depression, anxiety disorders, and autism. GABAergic synapses are located on neuronal cell bodies and dendritic shafts as well as axon initial segments. This study demonstrates that giant ankyrin-G forms micron-scale domains on neuronal cell bodies and dendritic shafts, and promotes somatodendritic GABAergic synapse stability through interaction with GABARAP and inhibition of GABAA receptor endocytosis. This previously undescribed mechanism for regulating cell surface expression of GABAA receptors and maintaining GABAergic interneuron synapses offers a rationale for previous association of ankyrin-G genetic variation with neurodevelopmental disorders and psychiatric disease. GABAA-receptor-based interneuron circuitry is essential for higher order function of the human nervous system and is implicated in schizophrenia, depression, anxiety disorders, and autism. Here we demonstrate that giant ankyrin-G (480-kDa ankyrin-G) promotes stability of somatodendritic GABAergic synapses in vitro and in vivo. Moreover, giant ankyrin-G forms developmentally regulated and cell-type-specific micron-scale domains within extrasynaptic somatodendritic plasma membranes of pyramidal neurons. We further find that giant ankyrin-G promotes GABAergic synapse stability through opposing endocytosis of GABAA receptors, and requires a newly described interaction with GABARAP, a GABAA receptor-associated protein. We thus present a new mechanism for stabilization of GABAergic interneuron synapses and micron-scale organization of extrasynaptic membrane that provides a rationale for studies linking ankyrin-G genetic variation with psychiatric disease and abnormal neurodevelopment.
关键词：giant ankyrin-G ; GABAergic synapses ; extrasynaptic membrane ; GABARAP ; GABA_A receptor endocytosis