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

• DOI: 10.1523/jneurosci.5938-10.2011
• Publication Date: 2011-04-20T17:03:10Z
• Authors: Eszter Szabadits; Csaba Cserép; András Szőnyi; Yugo Fukazawa; Ryuichi Shigemoto; Masahiko Watanabe; Shigeyoshi Itohara; Tamás F. Freund; Gábor Nyiri
• Keywords: 0301 basic medicine; neurológia; Action Potentials; Neural Inhibition; Nitric Oxide Synthase Type I; Nitric Oxide; Hippocampus; Immunohistochemistry; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan; Electrophysiology; Mice; 03 medical and health sciences; 0302 clinical medicine; Guanylate Cyclase; pszichiátria; Synapses; Animals; Cyclic GMP; gamma-Aminobutyric Acid; Signal Transduction

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 nitric oxide (NO)–cGMP cascade triggered by NMDA receptor (NMDAR) activation plays a role in the control of hippocampal GABAergic transmission in mice. GABAergic synapses express neuronal nitric oxide synthase (nNOS) postsynaptically and NO receptors (NO-sensitive guanylyl cyclase) in the presynaptic terminals. We hypothesized that—similar to glutamatergic synapses—the Ca2+transients required to activate nNOS were provided by NMDA receptor activation. Indeed, administration of 5 μmNMDA 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–fracture 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 subregion specific in the mouse hippocampus.