title: Involvement of nitric oxide in depolarization-induced suppression of inhibition in hippocampal pyramidal cells during activation of cholinergic receptors.
abstract: Several types of neurons are able to regulate their synaptic inputs via releasing retrograde signal molecules, such as endocannabinoids or nitric oxide (NO). Here we show that, during activation of cholinergic receptors, retrograde signaling by NO controls CB1 cannabinoid receptor (CB1R)-dependent depolarization-induced suppression of inhibition (DSI). Spontaneously occurring IPSCs were recorded in CA1 pyramidal neurons in the presence of carbachol, and DSI was induced by a 1-s-long depolarization step. We found that, in addition to the inhibition of CB1Rs, blocking the NO signaling pathway at various points also disrupted DSI. Inhibitors of NO synthase (NOS) or NO-sensitive guanylyl cyclase (NO-sGC) diminished DSI, whereas a cGMP analog or an NO donor inhibited IPSCs and partially occluded DSI in a CB1R-dependent manner. Furthermore, an NO scavenger applied extracellularly or postsynaptically also decreased DSI, whereas L-arginine, the precursor for NO, prolonged it. DSI of electrically evoked IPSCs was also blocked by an inhibitor of NOS in the presence, but not in the absence, of carbachol. In line with our electrophysiological data, double immunohistochemical staining revealed an NO-donor-induced cGMP accumulation in CB1R-positive axon terminals. Using electron microscopy, we demonstrated the postsynaptic localization of neuronal NOS at symmetrical synapses formed by CB1R-positive axon terminals on pyramidal cell bodies, whereas NO-sGC was found in the presynaptic terminals. These electrophysiological and anatomical results in the hippocampus suggest that NO is involved in depolarization-induced CB1R-mediated suppression of IPSCs as a retrograde signal molecule and that operation of this cascade is conditional on cholinergic receptor activation.
authors: Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary.
authors: Judit K
authors: JK
authors: Makara
authors: István
authors: I
authors: Katona
authors: Gábor
authors: G
authors: Nyíri
authors: Beáta
authors: B
authors: Németh
authors: Catherine
authors: C
authors: Ledent
authors: Masahiko
authors: M
authors: Watanabe
authors: Jan
authors: J
authors: de Vente
authors: Tamás F
authors: TF
authors: Freund
authors: Norbert
authors: N
authors: Hájos
mesh_terms: D000818:Animals; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism / Q000648:ultrastructure; D011950:Receptors, Cholinergic / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D043884:Receptor, Cannabinoid, CB1; D011950:Receptors, Cholinergic; D009569:Nitric Oxide