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.
Keywords: Glutamate release; NMDA receptor; Presynaptic; Protein kinase A; Subunit composition; Tonic activation.