{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T13:02:33Z","timestamp":1792242153615,"version":"4.4.0"},"reference-count":69,"publisher":"American Physiological Society","issue":"2","funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation (NSF)","doi-asserted-by":"publisher","award":["IOS-1051734"],"award-info":[{"award-number":["IOS-1051734"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of South Dakota Division of Basic Biomedical Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurophysiology"],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:p>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<jats:sup>\u2212<\/jats:sup>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 (N<jats:sub>poly<\/jats:sub>) and mechanical (N<jats:sub>mech<\/jats:sub>) nociceptive synapses. In P synapses, blocking Cl<jats:sup>\u2212<\/jats:sup>export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In N<jats:sub>mech<\/jats:sub>neurons, which are depolarized by GABA due to an elevated Cl<jats:sup>\u2212<\/jats:sup>equilibrium potentials (E<jats:sub>Cl<\/jats:sub>), endocannabinoid-mediated depression was prevented by blocking Cl<jats:sup>\u2212<\/jats:sup>import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). N<jats:sub>poly<\/jats:sub>neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl<jats:sup>\u2212<\/jats:sup>import. Consequently, the primary role of elevated E<jats:sub>Cl<\/jats:sub>may be to protect N<jats:sub>poly<\/jats:sub>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 N<jats:sub>poly<\/jats:sub>synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of N<jats:sub>mech<\/jats:sub>synapses. These findings demonstrate a critical role of differences in Cl<jats:sup>\u2212<\/jats:sup>gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.<\/jats:p>","DOI":"10.1152\/jn.00235.2016","type":"journal-article","created":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T04:08:54Z","timestamp":1464235734000},"page":"619-628","source":"Crossref","is-referenced-by-count":22,"title":["Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids"],"prefix":"10.1152","volume":"116","author":[{"given":"Yanqing","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; and"},{"name":"Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, South 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