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The Journal of Neuroscience, September 19, 2007, 27(38):10211-10222; doi:10.1523/JNEUROSCI.2104-07.2007

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Cellular/Molecular
Involvement of Nitric Oxide in Depolarization-Induced Suppression of Inhibition in Hippocampal Pyramidal Cells during Activation of Cholinergic Receptors

Judit K. Makara,¹ István Katona,¹ Gábor Nyíri,¹ Beáta Németh,¹ Catherine Ledent,² Masahiko Watanabe,³ Jan de Vente,⁴ Tamás F. Freund,¹ and Norbert Hájos¹

¹Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, ²Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, 1070 Brussels, Belgium, ³Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, and ⁴European Graduate School of Neuroscience, Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands

Correspondence should be addressed to Dr. Norbert Hájos, Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary. Email: hajos{at}koki.hu

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.

Key words: synaptic plasticity; hippocampus; GABA; CB₁ receptor; cGMP; retrograde

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Received Dec. 22, 2006; revised July 18, 2007; accepted July 22, 2007.

Correspondence should be addressed to Dr. Norbert Hájos, Department of Cellular and Network Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary. Email: hajos{at}koki.hu

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