title: NMDA receptor activation enhances inhibitory GABAergic transmission onto hippocampal pyramidal neurons via presynaptic and postsynaptic mechanisms.
abstract: N-methyl-D-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABA(A) receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.
authors.affiliation: Department of Neurophysiology, Kagawa School of Pharmaceutical Sciences and Institute of Neuroscience, Tokushima Bunri University, Kagawa, Japan.
authors.forename: Jiu-Gang
authors.initials: JG
authors.lastname: Xue
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Masuoka
authors.forename: Xian-Di
authors.initials: XD
authors.lastname: Gong
authors.forename: Ken-Shiung
authors.initials: KS
authors.lastname: Chen
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: S K Alex
authors.initials: SK
authors.lastname: Law
authors.forename: Shiro
authors.initials: S
authors.lastname: Konishi
mesh_terms: D060848:Agatoxins; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000166:cytology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D060848:Agatoxins; D002121:Calcium Channel Blockers; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D018682:GABA Agents; D007093:Imidazoles; D016194:Receptors, N-Methyl-D-Aspartate; D013111:Spider Venoms; C083855:omega-agatoxin-Aa4b; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D005680:gamma-Aminobutyric Acid; D020866:omega-Conotoxin GVIA; D019331:NG-Nitroarginine Methyl Ester