Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission

Neuron. 2006 Nov 9;52(3):461-74. doi: 10.1016/j.neuron.2006.09.031.


Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biotinylation / methods
  • Blotting, Western / methods
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology*
  • Electric Stimulation / methods
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Expression / physiology*
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology
  • Long-Term Synaptic Depression / radiation effects
  • Models, Biological
  • Mutagenesis / physiology
  • N-Methylaspartate / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Neurons / radiation effects
  • Okadaic Acid / pharmacology
  • Patch-Clamp Techniques / methods
  • RNA Interference / physiology
  • Rats
  • Receptors, AMPA / physiology*
  • Statistics, Nonparametric
  • Synaptic Transmission / physiology*
  • Time Factors
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • activity regulated cytoskeletal-associated protein
  • Green Fluorescent Proteins
  • Okadaic Acid
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid