title: Gating the polarity of endocannabinoid-mediated synaptic plasticity by nitric oxide in the spinal locomotor network.
abstract: The final motor output underlying behavior arises from an appropriate balance between excitation and inhibition within neural networks. Retrograde signaling by endocannabinoids adapts synaptic strengths and the global activity of neural networks. In the spinal cord, endocannabinoids are mobilized postsynaptically from network neurons and act retrogradely on presynaptic cannabinoid receptors to potentiate the locomotor frequency. However, it is still unclear whether mechanisms exist within the locomotor networks that determine the sign of the modulation by cannabinoid receptors to differentially regulate excitation and inhibition. In this study, using the lamprey spinal cord in vitro, we first report that 2-AG (2-arachidonyl glycerol) is mobilized by network neurons and underlies a form of modulation that is embedded within the locomotor networks. We then show that the polarity of the endocannabinoid modulation is gated by nitric oxide to enable simultaneously potentiation of excitation and depression of inhibition within the spinal locomotor networks. Our results suggest that endocannabinoid and nitric oxide systems interact to mediate inversion of the polarity of synaptic plasticity within the locomotor networks. Thus, endocannabinoid and nitric oxide shift in the excitation-inhibition balance to set the excitability of the spinal locomotor network.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 177 77 Stockholm, Sweden.
authors.forename: Jianren
authors.initials: J
authors.lastname: Song
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kyriakatos
authors.forename: Abdeljabbar
authors.initials: A
authors.lastname: El Manira
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D005989:Glycerides / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D007798:Lampreys / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009415:Nerve Net / Q000166:cytology / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077403:Orlistat; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005989:Glycerides; C534333:JZL 184; D007783:Lactones; D018377:Neurotransmitter Agents; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D009569:Nitric Oxide; D016202:N-Methylaspartate; C094503:glyceryl 2-arachidonate; D000077403:Orlistat