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NR3A-containing NMDARs promote neurotransmitter release and spike timing–dependent plasticity

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.

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Figure 1: Both the presynaptic localization of NR1 and the biochemical expression of Mg2+-insensitive NMDAR subunits decrease during early visual cortex development.
Figure 2: Glutamate-sensitive preNMDARs containing NR2B, but not NR2A or NR2D, enhance spontaneous neurotransmitter release onto juvenile L2/3 pyramidal neurons.
Figure 3: The reduced Mg2+ sensitivity of NR3A-containing preNMDARs promotes spontaneous neurotransmitter release in juvenile V1.
Figure 4: NR3A-containing preNMDARs enhance evoked neurotransmitter release at L2/3 visual cortical synapses.
Figure 5: NR2B- and NR3A-containing preNMDARs promote tLTD in juvenile V1.

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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.).

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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.

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Correspondence to Benjamin D Philpot.

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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

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