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NMDA Receptors Containing GluN2B/2C/2D Subunits Mediate an Increase in Glutamate Release at Hippocampal CA3–CA1 Synapses

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Abstract

NMDA receptors (NMDARs) are involved in synaptic transmission and synaptic plasticity in different brain regions, and they modulate glutamate release at different presynaptic sites. Here, we studied whether non-postsynaptic NMDARs, putatively presynaptic (preNMDARs), are tonically active at hippocampal CA3–CA1 synapses, and if they modulate glutamate release. We found that when postsynaptic NMDARs are blocked by MK801, D-AP5 depresses evoked and spontaneous excitatory synaptic transmission, indicating that preNMDARs are tonically active at CA3–CA1 synapses, facilitating glutamate release. The subunit composition of these NMDARs was determined by studying evoked and spontaneous excitatory synaptic transmission in the presence of Zn2+, Ro 25-6981, and PPDA, antagonists of NMDARs containing GluN2A, GluN2B, and GluN2C/D, respectively. We found that evoked and spontaneous release decreased when the activity of NMDARs containing GluN2B and GluN2C/D subunits but not GluN2A was impeded. In addition, we found that the increase in glutamate release mediated by these NMDARs requires protein kinase A (PKA) activation. We conclude that preNMDARs that contain GluN2B and GluN2C/2D subunits facilitate glutamate release at hippocampal CA3–CA1 synapses through a mechanism that involves PKA.

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Acknowledgments

We thank Dr. Cristina Calvino for her technical assistance and Dr. Mark Sefton for editorial assistance. This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO)/FEDER (BFU2012-38208), Ministerio de Economía, Industria y Competitividad/FEDER (BFU2015-68655-P), and the Junta de Andalucía (P11-CVI-7290) to A.R.M. J.P.-M and M.P.-R. were supported by a PhD Fellowship from the Plan Propio UPO. Y.A.-T. was supported by a Postdoctoral Fellowship from the Junta de Andalucía (Spain).

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  1. Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, ES-41013, Seville, Spain

    J. Prius-Mengual, M. Pérez-Rodríguez, Y. Andrade-Talavera & A. Rodríguez-Moreno

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  1. J. Prius-Mengual
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  2. M. Pérez-Rodríguez
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  3. Y. Andrade-Talavera
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J.P.-M., M.P.-R., and Y.A.-T. performed the electrophysiological experiments and analyzed the data. A.R.-M. conceived the study and wrote the manuscript. All the authors have read and approved the final version of the manuscript submitted.

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Correspondence to A. Rodríguez-Moreno.

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Prius-Mengual, J., Pérez-Rodríguez, M., Andrade-Talavera, Y. et al. NMDA Receptors Containing GluN2B/2C/2D Subunits Mediate an Increase in Glutamate Release at Hippocampal CA3–CA1 Synapses. Mol Neurobiol 56, 1694–1706 (2019). https://doi.org/10.1007/s12035-018-1187-5

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