Abstract
Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the NR3A subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that NR3A is required for spike timing–dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, NR2B-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that NR3A relieves preNMDARs from the dual-activation requirement of ligand-binding and depolarization; the developmental removal of NR3A limits preNMDAR functionality by restoring this associative property.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hensch, T.K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).
Philpot, B.D., Sekhar, A.K., Shouval, H.Z. & Bear, M.F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).
Dudek, S.M. & Bear, M.F. Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus. J. Neurosci. 13, 2910–2918 (1993).
Corlew, R., Wang, Y., Ghermazien, H., Erisir, A. & Philpot, B.D. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J. Neurosci. 27, 9835–9845 (2007).
Banerjee, A. et al. Double dissociation of spike timing–dependent potentiation and depression by subunit-preferring NMDA receptor antagonists in mouse barrel cortex. Cereb. Cortex 19, 2959–2969 (2009).
Kemp, J.A. & McKernan, R.M. NMDA receptor pathways as drug targets. Nat. Neurosci. 5 Suppl: 1039–1042 (2002).
Cull-Candy, S.G. & Leszkiewicz, D.N. Role of distinct NMDA receptor subtypes at central synapses. Sci. STKE 2004, re16 (2004).
Rodríguez-Moreno, A., Banerjee, A. & Paulsen, O. Presynaptic NMDA receptors and spike timing-dependent long-term depression at cortical synapses. Front. Synaptic Neurosci 2, 12 (2010).
Corlew, R., Brasier, D.J., Feldman, D.E. & Philpot, B.D. Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity. Neuroscientist 14, 609–625 (2008).
Sjöström, P.J., Turrigiano, G.G. & Nelson, S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39, 641–654 (2003).
Brasier, D.J. & Feldman, D.E. Synapse-specific expression of functional presynaptic NMDA receptors in rat somatosensory cortex. J. Neurosci. 28, 2199–2211 (2008).
Bender, V.A., Bender, K.J., Brasier, D.J. & Feldman, D.E. Two coincidence detectors for spike timing–dependent plasticity in somatosensory cortex. J. Neurosci. 26, 4166–4177 (2006).
Berretta, N. & Jones, R.S. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 75, 339–344 (1996).
Rodríguez-Moreno, A. & Paulsen, O. Spike timing–dependent long-term depression requires presynaptic NMDA receptors. Nat. Neurosci. 11, 744–745 (2008).
Yang, J., Woodhall, G.L. & Jones, R.S. Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats. J. Neurosci. 26, 406–410 (2006).
Henson, M.A., Roberts, A.C., Perez-Otano, I. & Philpot, B.D. Influence of the NR3A subunit on NMDA receptor functions. Prog. Neurobiol. 91, 23–37 (2010).
Karavanova, I., Vasudevan, K., Cheng, J. & Buonanno, A. Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice. Mol. Cell. Neurosci. 34, 468–480 (2007).
Nishi, M., Hinds, H., Lu, H.P., Kawata, M. & Hayashi, Y. Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. J. Neurosci. 21, RC185 (2001).
Wong, H.K. et al. Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J. Comp. Neurol. 450, 303–317 (2002).
Roberts, A.C. et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63, 342–356 (2009).
Laurie, D.J. & Seeburg, P.H. Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition. Eur. J. Pharmacol. 268, 335–345 (1994).
Laube, B., Hirai, H., Sturgess, M., Betz, H. & Kuhse, J. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 18, 493–503 (1997).
Costa, B.M. et al. N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives: preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3–CA1 synapse. J. Pharmacol. Exp. Ther. 331, 618–626 (2009).
Charton, J.P., Herkert, M., Becker, C.M. & Schroder, H. Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res. 816, 609–617 (1999).
DeBiasi, S., Minelli, A., Melone, M. & Conti, F. Presynaptic NMDA receptors in the neocortex are both auto- and heteroreceptors. Neuroreport 7, 2773–2776 (1996).
Li, Y.H., Wang, J. & Zhang, G. Presynaptic NR2B-containing NMDA autoreceptors mediate glutamatergic synaptic transmission in the rat visual cortex. Curr. Neurovasc. Res. 6, 104–109 (2009).
Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996).
Pérez-Otaño, I. et al. Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nat. Neurosci. 9, 611–621 (2006).
Cheetham, C.E. & Fox, K. Presynaptic development at L4 to l2/3 excitatory synapses follows different time courses in visual and somatosensory cortex. J. Neurosci. 30, 12566–12571 (2010).
Larsen, R.S., Rao, D., Manis, P.B. & Philpot, B.D. STDP in the developing sensory neocortex. Front. Synaptic Neurosci. 2, 12 (2010).
Froemke, R.C., Poo, M.M. & Dan, Y. Spike timing–dependent synaptic plasticity depends on dendritic location. Nature 434, 221–225 (2005).
McKinney, R.A., Capogna, M., Durr, R., Gahwiler, B.H. & Thompson, S.M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat. Neurosci. 2, 44–49 (1999).
Smith, S.L. & Trachtenberg, J.T. Experience-dependent binocular competition in the visual cortex begins at eye opening. Nat. Neurosci. 10, 370–375 (2007).
Hatton, C.J. & Paoletti, P. Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron 46, 261–274 (2005).
Smothers, C.T. & Woodward, J.J. Effect of the NR3 subunit on ethanol inhibition of recombinant NMDA receptors. Brain Res. 987, 117–121 (2003).
Pérez-Otaño, I. et al. Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J. Neurosci. 21, 1228–1237 (2001).
Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998).
Yao, Y. & Mayer, M.L. Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J. Neurosci. 26, 4559–4566 (2006).
Piña-Crespo, J.C. et al. Excitatory glycine responses of CNS myelin mediated by NR1/NR3 “NMDA” receptor subunits. J. Neurosci. 30, 11501–11505 (2010).
Chatterton, J.E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002).
Herkert, M., Rottger, S. & Becker, C.M. The NMDA receptor subunit NR2B of neonatal rat brain: complex formation and enrichment in axonal growth cones. Eur. J. Neurosci. 10, 1553–1562 (1998).
McGuinness, L. et al. Presynaptic NMDARs in the hippocampus facilitate transmitter release at theta frequency. Neuron 68, 1109–1127 (2010).
Mameli, M., Carta, M., Partridge, L.D. & Valenzuela, C.F. Neurosteroid-induced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors. J. Neurosci. 25, 2285–2294 (2005).
Christie, J.M. & Jahr, C.E. Dendritic NMDA receptors activate axonal calcium channels. Neuron 60, 298–307 (2008).
Christie, J.M. & Jahr, C.E. Selective expression of ligand-gated ion channels in L5 pyramidal cell axons. J. Neurosci. 29, 11441–11450 (2009).
Lin, H. et al. Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons. Proc. Natl. Acad. Sci. USA 107, 16661–16666 (2010).
Ikeda, K. et al. Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel. Brain Res. Mol. Brain Res. 33, 61–71 (1995).
Li, Y.H. & Han, T.Z. Glycine binding sites of presynaptic NMDA receptors may tonically regulate glutamate release in the rat visual cortex. J. Neurophysiol. 97, 817–823 (2007).
Kharazia, V.N. & Weinberg, R.J. Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J. Comp. Neurol. 412, 292–302 (1999).
Jacob, A.L., Jordan, B.A. & Weinberg, R.J. Organization of amyloid-beta protein precursor intracellular domain-associated protein-1 in the rat brain. J. Comp. Neurol. 518, 3221–3236 (2010).
Acknowledgements
We thank K. Phend and S. Burette for processing electron microscopic materials and P. McCoy and T. Riday for preparing fixed tissue for this process. We also thank J. Miriyala, J. Berrios and K. Williams for mouse colony maintenance and genotyping. We thank D.J. Brasier, T. Kash, N. Calakos and D. Corlew for early critical readings of the manuscript and R. Chitwood for technical assistance. This work was supported by National Alliance for Research on Schizophrenia and Depression, the Marie Curie International Program, UTE project Centro de Investigación Médica Aplicada, and Spanish Ministry of Education and Science grants SAF2006-10025, CSD2008-00005 (to I.P.-O.), National Research Service Award predoctoral fellowship F31 GM080162 (to R.J.C.), a University of North Carolina dissertation completion fellowship (to M.A.H.), a National Institute of Child Health and Human Development training grant (T32 HD40127) and NARSAD Fellowships (to A.C.R.), US National Institutes of Health grant RO1 NS39444 (to R.J.W.), NARSAD, NEI R01 EY018323, and National Science Foundation grant 0822969 (to B.D.P.), and P01 HD29587, R01 EY05477 and R01 EY09024 (to S.A.L.).
Author information
Authors and Affiliations
Contributions
R.S.L., R.J.C., R.J.W. and B.D.P. designed the study. R.S.L. performed whole-cell recordings of mEPSCs, evoked release, and tLTD in all genotypes and conditions and wrote the manuscript. R.J.C. performed the majority of mEPSC recordings in low Mg2+, analyzed immunogold NR1 labeling, contributed to mEPSC recordings in Nr3a−/− and NR3A-overexpressing mice, and helped to prepare the figures and manuscript. M.A.H. performed all biochemical fractionation and quantitative immunoblotting. A.C.R. performed recordings of evoked responses in the presence of UBP141 and contributed to mEPSC recordings in NR3A-overexpressing mice. M.M. provided Nr2d−/− mice. M.W. designed and provided the antibody to NR3A that was used for immunoperoxidase labeling. S.A.L. and N.N. provided Nr3a−/− mice, edited the manuscript and provided experimental suggestions. I.P.-O. provided NR3A-overexpressing mice and performed immunohistochemistry on these mice. R.J.W. helped to prepare the manuscript and performed immunogold and immunoperoxidase labeling for NR1 and NR3A. B.D.P. supervised the entire study and edited the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–11 (PDF 7558 kb)
Rights and permissions
About this article
Cite this article
Larsen, R., Corlew, R., Henson, M. et al. NR3A-containing NMDARs promote neurotransmitter release and spike timing–dependent plasticity. Nat Neurosci 14, 338–344 (2011). https://doi.org/10.1038/nn.2750
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2750
This article is cited by
-
Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain
Nature Communications (2022)
-
Aberrant maturation and connectivity of prefrontal cortex in schizophrenia—contribution of NMDA receptor development and hypofunction
Molecular Psychiatry (2022)
-
NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice
Molecular Brain (2021)
-
Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
Nature Communications (2020)
-
Multiplexed and high-throughput neuronal fluorescence imaging with diffusible probes
Nature Communications (2019)