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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ankyrins / genetics
  • Ankyrins / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Endocytosis*
  • GABAergic Neurons / metabolism*
  • GABAergic Neurons / pathology
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mental Disorders / genetics
  • Mental Disorders / metabolism
  • Mental Disorders / pathology
  • Mice
  • Pyramidal Cells / metabolism*
  • Pyramidal Cells / pathology
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism*
  • Synaptic Membranes / pathology

Substances

  • Ank3 protein, mouse
  • Ankyrins
  • Cytoskeletal Proteins
  • GABARAP protein, mouse
  • Membrane Proteins
  • Receptors, GABA-A