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Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1214-9. doi: 10.1073/pnas.1417989112. Epub 2014 Dec 31.

Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
2
Howard Hughes Medical Institute and Department of Biochemistry, Duke University, Durham, NC 27710; and.
3
Department of Neurobiology, Duke University, Durham, NC 27710.
4
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.

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.

KEYWORDS:

GABAA receptor endocytosis; GABARAP; GABAergic synapses; extrasynaptic membrane; giant ankyrin-G

PMID:
25552561
PMCID:
PMC4313813
DOI:
10.1073/pnas.1417989112
[Indexed for MEDLINE]
Free PMC Article

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