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PLoS One. 2018 Feb 13;13(2):e0192242. doi: 10.1371/journal.pone.0192242. eCollection 2018.

The siRNA-mediated knockdown of GluN3A in 46C-derived neural stem cells affects mRNA expression levels of neural genes, including known iGluR interactors.

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The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
Department of Biochemistry I - Receptor Biochemistry, Ruhr University Bochum, Bochum, Germany.
International Graduate School of Neuroscience, Ruhr University Bochum, Bochum, Germany.
Ruhr University Research School, Ruhr University Bochum, Bochum, Germany.
CNRS UMR8246, Université Pierre et Marie Curie, Paris, France.
German Cancer Research Center, Heidelberg, Germany.
Fraunhofer Institute for Molecular Biology and Applied Ecology, Schmallenberg, Germany.
Department of Biochemistry II - Molecular Neurobiochemistry, Ruhr University Bochum, Bochum, Germany.
Department of Biochemistry II - Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany.
Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, Seattle, Washington, United States of America.


For years, GluN3A was solely considered to be a dominant-negative modulator of NMDARs, since its incorporation into receptors alters hallmark features of conventional NMDARs composed of GluN1/GluN2 subunits. Only recently, increasing evidence has accumulated that GluN3A plays a more diversified role. It is considered to be critically involved in the maturation of glutamatergic synapses, and it might act as a molecular brake to prevent premature synaptic strengthening. Its expression pattern supports a putative role during neural development, since GluN3A is predominantly expressed in early pre- and postnatal stages. In this study, we used RNA interference to efficiently knock down GluN3A in 46C-derived neural stem cells (NSCs) both at the mRNA and at the protein level. Global gene expression profiling upon GluN3A knockdown revealed significantly altered expression of a multitude of neural genes, including genes encoding small GTPases, retinal proteins, and cytoskeletal proteins, some of which have been previously shown to interact with GluN3A or other iGluR subunits. Canonical pathway enrichment studies point at important roles of GluN3A affecting key cellular pathways involved in cell growth, proliferation, motility, and survival, such as the mTOR pathway. This study for the first time provides insights into transcriptome changes upon the specific knockdown of an NMDAR subunit in NSCs, which may help to identify additional functions and downstream pathways of GluN3A and GluN3A-containing NMDARs.

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