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

• Published in: The Journal of biological chemistry 2020-06, Vol.295 (25), p.8613-8627
• Main Authors: Chen, Liang-Fu, Lyons, Michelle R., Liu, Fang, Green, Matthew V., Hedrick, Nathan G., Williams, Ashley B., Narayanan, Arthy, Yasuda, Ryohei, West, Anne E.
• Format: Article
• Language: English
• Subjects: Animals; brain-derived neurotrophic factor (BDNF); Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Calcium - metabolism; Cell Nucleus - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; excitation-transcription coupling; Female; gene regulation; glutamate receptor ionotropic NMDA (GluN); Hippocampus - metabolism; ionotropic glutamate receptor; Male; MEF2 transcription factors; MEF2 Transcription Factors - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; mitogen-activated protein kinase (MAPK) signaling; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; neurodevelopment; Neuronal Plasticity - physiology; NMDAR; N‐methyl‐d‐aspartate receptor (NMDA receptor; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction; synaptic activity; Tetrodotoxin - pharmacology; Transcription, Genetic - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.010266

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.