NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors

J Neurosci. 2007 Dec 26;27(52):14326-37. doi: 10.1523/JNEUROSCI.4433-07.2007.

Abstract

The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA(A) receptors (GABA(A)Rs) are also subject to regulation and that GABA(A)R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases expression of GABA(A)Rs at the dendritic surface of hippocampal neurons. This NMDA stimulus increases miniature IPSC amplitudes and requires the activity of Ca2+ calmodulin-dependent kinase II and the trafficking proteins N-ethylmaleimide-sensitive factor, GABA receptor-associated protein (GABARAP), and glutamate receptor interacting protein (GRIP). These data demonstrate for the first time that endogenous GABARAP and GRIP contribute to the regulated trafficking of GABA(A)Rs. In addition, they reveal that the bidirectional trafficking of AMPA and GABA(A) receptors can be driven by a single glutamatergic stimulus, providing a potent postsynaptic mechanism for modulating neuronal excitability.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Biotinylation / methods
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Exocytosis / drug effects
  • Exocytosis / physiology*
  • Glutamate Decarboxylase / metabolism*
  • Hippocampus / cytology
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Inhibitory Postsynaptic Potentials / radiation effects
  • Microtubule-Associated Proteins / metabolism*
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques / methods
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / physiology*
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • GABARAP protein, rat
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Receptors, GABA
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1