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

Chen, Liang-Fu; Lyons, Michelle R.; Liu, Fang; Green, Matthew V.; Hedrick, Nathan G.; Williams, Ashley B.; Narayanan, Arthy; Yasuda, Ryohei; West, Anne E.

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

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Hedrick, Nathan G.
Max Planck Florida Institute for Neuroscience, Max Planck Society;

Yasuda, Ryohei
Max Planck Florida Institute for Neuroscience, Max Planck Society;

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Citation

Chen, L.-F., Lyons, M. R., Liu, F., Green, M. V., Hedrick, N. G., Williams, A. B., 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, (25), 8613-8627. Retrieved from https://www.jbc.org/article/S0021925817492544/pdf.

Cite as: https://hdl.handle.net/21.11116/0000-000C-DF9D-9

Abstract

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.