NMDA Receptors in Hippocampal GABAergic Synapses and Their Role in Nitric Oxide Signaling

GABAergic inhibition plays a central role in the control of pyramidal cell ensemble activities, thus, any signaling mechanism that regulates inhibition is able to fine-tune network patterns. Here we provide evidence that the retrograde NO-cGMP cascade triggered by NMDA-receptor activation plays a role in the control of hippocampal GABAergic transmission in mice. GABAergic synapses express nNOS postsynaptically and NO receptors (NO-sensitive guanylyl cyclase) in the presynaptic terminals. We hypothesised that – similar to glutamatergic synapses – the Ca(2+) transients required to activate nNOS were provided by NMDA receptor activation. Indeed, administration of 5μM NMDA induced a robust nNOS-dependent cGMP production in GABAergic terminals, selectively in the CA1 and CA3c areas. Furthermore, using preembedding, postembedding and SDS-digested freeze-facture replica immunogold labeling, we provided quantitative immunocytochemical evidence that NMDAR subunits GluN1, GluN2A and GluN2B were present in most somatic GABAergic synapses postsynaptically. These data indicate that NMDARs can modulate hippocampal GABAergic inhibition via NO-cGMP signaling in an activity-dependent manner, and that this effect is sub-region specific in the mouse hippocampus