AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc

Nat Neurosci. 2006 Jul;9(7):887-95. doi: 10.1038/nn1708. Epub 2006 May 28.


Learning and memory depend critically on long-term synaptic plasticity, which requires neuronal gene expression. In the prevailing view, AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but they do not directly regulate neuronal gene expression. By studying regulation of Arc, a gene required for long-term plasticity, we uncovered a new role for AMPA receptors in neuronal gene expression. Spontaneous synaptic activity or activity induced by brain-derived neurotrophic factor (BDNF) elicited Arc expression in cultures of rat cortical neurons and in organotypic brain slices. Notably, inhibiting AMPA receptors strongly potentiated activity-dependent Arc expression. We found that AMPA receptors negatively regulate Arc transcription, but not translation or stability, through a mechanism involving a pertussis toxin-sensitive G protein. These results provide insights into the activity-dependent mechanisms of Arc expression and suggest that, in addition to effecting short-term plasticity, AMPA receptors regulate genes involved in long-term plasticity.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Bicuculline / pharmacology
  • Blotting, Northern / methods
  • Blotting, Western / methods
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Antagonists / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / physiology*
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • In Vitro Techniques
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Neurons / drug effects
  • Neurons / physiology
  • Rats
  • Receptors, AMPA / physiology*
  • Transfection / methods


  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • activity regulated cytoskeletal-associated protein
  • Calcium
  • Bicuculline