title: Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids.
abstract: Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota bburrell@usd.edu.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Burrell
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D002034:Bumetanide / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002211:Capsaicin / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000166:cytology; D002712:Chlorides / Q000378:metabolism*; D002934:Cinnamates / Q000494:pharmacology; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D007783:Lactones / Q000494:pharmacology; D007865:Leeches; D009474:Neurons / Q000187:drug effects*; D000077403:Orlistat; D018408:Patch-Clamp Techniques; D018689:Sensory System Agents / Q000494:pharmacology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013569:Synapses / Q000145:classification* / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000813:Anilides; D063385:Cannabinoid Receptor Modulators; D002712:Chlorides; D002934:Cinnamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D007783:Lactones; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D018689:Sensory System Agents; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D005680:gamma-Aminobutyric Acid; D000077403:Orlistat; D002211:Capsaicin
keywords: Cl− homeostasis; Hirudo; TRPV; endocannabinoids; neuromodulation