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


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 sequencing, 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 (MAP) 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.





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Publication Info

Chen, Liang-Fu, Michelle R Lyons, Fang Liu, Matthew V Green, Nathan G Hedrick, Ashley B Williams, Arthy Narayanan, Ryohei Yasuda, et al. (2020). The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription. The Journal of biological chemistry. pp. jbc.RA119.010266–jbc.RA119.010266. 10.1074/jbc.ra119.010266 Retrieved from

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Anne Elizabeth West

Professor of Neurobiology

The long term goal of our laboratory is to understand at a cellular/molecular level how neuronal activity regulates the formation and maturation of synapses during brain development, and ultimately to use genetic model systems to understand how defects in this developmental process lead to cognitive dysfunction.

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