title: NMDA receptors in hippocampal GABAergic synapses and their role in nitric oxide signaling.
abstract: 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 Ca(2+) transients required to activate nNOS were provided by NMDA receptor activation. Indeed, administration of 5 μm 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-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.
authors.affiliation: Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Szabadits
authors.forename: Csaba
authors.initials: C
authors.lastname: Cserép
authors.forename: András
authors.initials: A
authors.lastname: Szonyi
authors.forename: Yugo
authors.initials: Y
authors.lastname: Fukazawa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Tamás F
authors.initials: TF
authors.lastname: Freund
authors.forename: Gábor
authors.initials: G
authors.lastname: Nyiri
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004594:Electrophysiology; D006162:Guanylate Cyclase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D052248:Nitric Oxide Synthase Type I; D006162:Guanylate Cyclase; D006152:Cyclic GMP