The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription

J Biol Chem. 2020 Jun 19;295(25):8613-8627. doi: 10.1074/jbc.RA119.010266. Epub 2020 May 11.


N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons.

Keywords: MEF2 transcription factors; NMDAR); N‐methyl‐d‐aspartate receptor (NMDA receptor; brain-derived neurotrophic factor (BDNF); excitation-transcription coupling; gene regulation; glutamate receptor ionotropic NMDA (GluN); ionotropic glutamate receptor; mitogen-activated protein kinase (MAPK) signaling; neurodevelopment; p38 MAPK; synaptic activity.

Publication types

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

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium / metabolism
  • Cell Nucleus / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Female
  • Hippocampus / metabolism
  • MEF2 Transcription Factors / metabolism
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / physiology*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Tetrodotoxin / pharmacology
  • Transcription, Genetic* / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • Grin3a protein, rat
  • MEF2 Transcription Factors
  • MEF2C protein, rat
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • activity regulated cytoskeletal-associated protein
  • Tetrodotoxin
  • p38 Mitogen-Activated Protein Kinases
  • Calcium