Prius Mengual, JoséPérez Rodríguez, MikelAndrade Talavera, YunieskyRodríguez-Moreno, Antonio2025-04-022025-04-022019Prius-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/s12035-018-1187-510.1007/s12035-018-1187-5https://hdl.handle.net/10433/23705NMDA 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.application/pdfenAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Glutamate releaseNMDA receptorPresynapticProtein kinase ASubunit compositionTonic activationjournal articlerestricted access