title: Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
authors.forename: Wei Chou
authors.initials: WC
authors.lastname: Tseng
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Duke University, Durham, NC 27710; and.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jenkins
authors.affiliation: Department of Neurobiology, Duke University, Durham, NC 27710.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Neurobiology, Duke University, Durham, NC 27710.
authors.forename: Richard
authors.initials: R
authors.lastname: Mooney
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Duke University, Durham, NC 27710; and Department of Neurobiology, Duke University, Durham, NC 27710 vann.bennett@dm.duke.edu.
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D059330:GABAergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D051017:Apoptosis Regulatory Proteins; D003598:Cytoskeletal Proteins; C480861:GABARAP protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011963:Receptors, GABA-A
keywords: GABAA receptor endocytosis; GABARAP; GABAergic synapses; extrasynaptic membrane; giant ankyrin-G