Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB

Neurosci Lett. 2017 Nov 20:661:23-28. doi: 10.1016/j.neulet.2017.09.024. Epub 2017 Sep 14.


Arc/Arg3.1 is a unique immediate early gene whose expression is highly dynamic and correlated with various forms of synaptic plasticity. Many previous reports highlight the complexity of mechanisms that regulate Arc/Arg3.1 expression in neurons. In the present study, the expression and regulation of Arc/Arg3.1 after glutamate treatment in primary cultured cortical neurons were investigated. We found that both Arc/Arg3.1 mRNA and Arc/Arg3.1 protein dynamically increased within 24h after glutamate treatment. The results of immunostaining showed that abundant amounts of Arc/Arg3.1 protein are presented in both soma and dendrites. The glutamate-induced increase in Arc/Arg3.1 protein levels was partially prevented by the NMDAR inhibitor DL-AP5, but not the AMPAR inhibitor NBQX. The results of calcium imaging showed that glutamate induced significant increases in intracellular calcium levels in a NMDAR-dependent manner. However, the intracellular calcium chelator BAPTA-AM had no effect on glutamate-induced upregulation of Arc/Arg3.1 protein, and alteration of cytosolic calcium ion homeostasis with A23187 and TG did not change Arc/Arg3.1 protein levels. In addition, the phosphorylation of ERK and CREB, two downstream factors of NMDAR signaling, markedly increased after glutamate exposure. Blocking ERK and CREB activation via selective inhibitors partially prevented the glutamate-induced elevation of Arc/Arg3.1 protein levels. Combined observations support a NMDAR-mediated and calcium-independent mechanism by which glutamate increases Arc/Arg3.1 expression in cortical neurons.

Keywords: Arc/Arg3.1; CREB; ERK; Glutamate receptor; Immediate early gene.

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytoskeletal Proteins / drug effects
  • Cytoskeletal Proteins / metabolism
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Genes, Immediate-Early / drug effects
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • MAP Kinase Signaling System / drug effects
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Cyclic AMP Response Element-Binding Protein
  • Cytoskeletal Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid