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March 2020 Revised Grin3a Clean Copy The NMDA receptor subunit GluN3A regulates synaptic activity-induced and MEF2C- dependent transcription Liang-Fu Chen1, Michelle R. Lyons1, Fang Liu1, Matthew V. Green1, Nathan G. Hedrick1, Ashley B. Williams1, Arthy Narayanan1, Ryohei Yasuda2, and Anne E. West1* 1Department of Neurobiology, Duke University Medical Center, Durham, NC 27710 USA 2Max Planck Florida Institute for Neuroscience, Jupiter, FL 33458 USA Running title: GluN3A-regulated neuronal transcription *To whom correspondence should be addressed: Anne E. West, Department of Neurobiology, Duke University Medical Center, 311 Research Dr., DUMC Box 3209, Bryan Research 301D, Durham, NC 27710. 919-681-1909, [email protected] Keywords: N‐methyl‐D‐aspartate receptor (NMDA receptor, NMDAR); p38 MAPK; excitation- transcription coupling; neurodevelopment, brain-derived neurotrophic factor (BDNF) ______________________________________________________________________________ ABSTRACT program of synaptic activity-regulated gene N-methyl-D-aspartate type glutamate transcription in developing neurons. receptors (NMDARs) are key mediators of ____________________________________ synaptic activity-regulated gene transcription in neurons, both during development and in N-methyl-D-aspartate type glutamate the adult brain. Developmental differences in receptors (NMDARs) are essential for the GluN2 subunit composition of NMDARs coupling sensory experience with brain determines whether NMDARs activate the development. In addition to functioning as transcription factor CREB. However, ligand-gated ionotropic receptors, NMDARs whether the developmentally-regulated exert long-lasting effects on neuronal biology GluN3A subunit also modulates NMDAR- by activating intracellular signaling cascades induced transcription was unknown. Here we that subsequently impact synapse formation, show that knocking down GluN3A in rat maturation, and function. These inductive hippocampal neurons promotes the inducible effects of NMDARs are mediated at least in transcription of a subset of NMDAR- part by the regulation of programs of gene sensitive genes. This enhancement is transcription. The targets of NMDAR- mediated by the accumulation of regulated transcriptional signaling cascades phosphorylated p38 MAP kinase in the in neurons include genes like Bdnf and Arc nucleus, which drives the activation of the that directly alter synapse development and transcription factor MEF2C and promotes the function, providing a compelling mechanism transcription of a subset of synaptic activity- for activity-induced synaptic development induced genes including Bdnf and Arc. Our and plasticity (1). evidence that GluN3A negatively regulates NMDARs are heterotetrameric MEF2C-dependent transcription reveals a receptors, all of which contain the obligatory novel mechanism by which NMDAR subunit GluN1 pore-forming subunit in varying composition confers specificity on the stoichiometries with the glutamate-binding GluN3A-regulated neuronal transcription GluN2 (A-D) subunits and the modulatory Although these data indicate that GluN3A is GluN3 (A-B) subunits (2). In addition to a negative regulator of synapse maturation, determining the biophysical properties of the mechanism of its action in has remained NMDA receptors (e.g. conductance, to be fully understood. magnesium sensitivity, calcium We identified the transcription factor permeability), subunit composition CaRF as an upstream regulator of GluN3A influences the specificity of the downstream expression (18). CaRF knockout mice show signaling cascades initiated following enhanced NMDAR-induced transcription of receptor activation largely via protein-protein Bdnf both in culture and in vivo in a manner interactions with the highly variable subunit that correlates with reduced GluN3A C-terminal tails (3,4). Unlike the ubiquitous expression (18), raising the possibility that expression of the GluN1 subunit, the GluN2 GluN3A may function to transiently inhibit and GluN3 subunits show substantial the NMDAR-dependent induction of Bdnf regional and developmental regulation of and other neuronal activity-regulated genes their expression in the brain, suggesting a in developing neurons. Here to determine the mechanism for NMDAR functional diversity. function of GluN3A in NMDAR-dependent The ratio of GluN2A to GluN2B subunits is transcription, we knocked down the dynamic during postnatal development (5) expression of GluN3A in primary rat and has been shown to modulate the hippocampal neurons and determined the activation of transcriptional programs by consequences for NMDAR-induced NMDARs as neurons age (6,7). Specifically, programs of gene expression. We find that GluN2A, which predominates at synaptic GluN3A limits the NMDAR-activation of a receptors and in older neurons, promotes cell select group of genes including Bdnf and Arc. survival via the phosphorylation/activation of GluN3A impacts downstream gene the transcription factor CREB; whereas transcription by inhibiting the nuclear GluN2B, which is more widely expressed in translocation of the p38 mitogen-activated younger neurons and preferentially found at protein kinase (MAPK), which is required for extrasynaptic receptors, activates signaling the activation of genes that depend on the cascades that lead to CREB transcription factor MEF2C. The net effect of dephosphorylation and cell death (8,9). this pathway is to confer specificity upon the Neurons in the developing postnatal set of synaptic signaling pathways that can brain also transiently express high levels of induce activity-dependent transcription in the GluN3A subunit, which is incorporated developing neurons. These data bring new into functional GluN1-GluN2-GluN3 understanding to the mechanisms by which glutamate-activated NMDARs (10-13). NMDARs regulate activity-dependent brain Genetic deletion of GluN3A is associated development. with dysregulation of the plasticity of glutamatergic synapses in the developing RESULTS brain, implicating the expression of this Knockdown of GluN3A potentiates NMDAR- subunit in NMDAR-dependent aspects of dependent induction of Bdnf brain development (14,15). Functionally, To test the requirement for GluN3A excitatory synapses show evidence of in NMDAR-inducible transcription of Bdnf, premature maturation in GluN3A knockout we characterized two independent shRNAs in mice (15,16), whereas prolonging expression lentivirus that robustly knockdown (KD) the of GluN3A into adulthood causes excitatory expression of Grin3a mRNA and GluN3A synapses to persist in a juvenile state (17). protein in cultured embryonic rat 2 GluN3A-regulated neuronal transcription hippocampal neurons, and generated a levels (Fig. 1F). To determine whether TTX GluN3A rescue construct that is resistant to w/d induced changes in Bdnf mRNA shRNA1 (Fig. 1A-C). To activate NMDARs, induction are sufficient to result in changes in we silenced neurons with TTX for 48 hours BDNF protein, we performed BDNF ELISA and then acutely withdrew TTX (TTX w/d), assays. TTX w/d induced the expression of which induces rebound firing, glutamate BDNF protein in all samples (Fig. 1G). release, and NMDAR-dependent changes in Similar to the effects of GluN3A KD on Bdnf gene transcription (Fig. S1) (19). As we exon IV mRNA induction, GluN3A KD reported previously in mouse cortical neurons showed a significantly greater neurons (18), TTX w/d from rat hippocampal induction of BDNF protein after TTX w/d neurons significantly induces the NMDAR- compared with control, whereas the dependent expression of exon IV-containing coexpression of the GluN3A rescue restored forms of Bdnf, which are produced by the BDNF protein induction to control levels. activation of Bdnf promoter IV (Fig. S1) (20). In the context of Knockdown of GluN3A with either of the GluN1/GluN2/GluN3 NMDARs, GluN3 has two shRNAs had no significant effect on been reported to lower calcium permeability Bdnf IV levels in TTX silenced neurons but (15). To determine whether our resulted in a significant potentiation of Bdnf manipulations of GluN3A expression in IV mRNA transcription upon TTX w/d for hippocampal neurons were affecting each shRNA compared with its paired control glutamate-induced calcium influx at infected neurons (Fig. 1D,E). The synapses, we performed two-photon potentiation of Bdnf promoter IV activation glutamate uncaging and dendritic spine in GluN3A KD neurons was selective for calcium imaging in organotypic rat transcription induced by NMDARs, because hippocampal slices. Local glutamate there were no significant differences in the uncaging led to a transient increase in spine fold change of Bdnf IV mRNA induced in calcium as detected by the calcium indicator GluN3A KD versus control neurons GCaMP3 (Fig. 1H). GluN3A KD neurons following KCl-mediated membrane showed a significantly greater increase in depolarization (Fig. S2A), which activates GCaMP3 fluorescence upon uncaging transcription selectively via the opening of L- compared with control pLKO vector type voltage-gated calcium channels transfected neurons, whereas co-expression (LVGCCs) and does not require the of the GluN3A rescue plasmid with the activation of NMDARs (18). Grin3a shRNA restored the calcium signal to To determine whether the enhanced control levels (Fig 1I-K). This evidence that activation of Bdnf IV transcription in GluN3A levels regulate glutamate-dependent GluN3A KD neurons is a direct result of the changes in spine calcium is consistent with absence of GluN3A, as opposed to an off- the possibility that GluN3A modulates target
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