{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T19:55:00Z","timestamp":1767902100601,"version":"3.49.0"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T00:00:00Z","timestamp":1510099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["F31\u2010NS080462"],"award-info":[{"award-number":["F31\u2010NS080462"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R56\u2010NS075278"],"award-info":[{"award-number":["R56\u2010NS075278"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["KL2\u2010TR001432"],"award-info":[{"award-number":["KL2\u2010TR001432"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008064","name":"Georgetown University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008064","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Homeostatic synaptic plasticity (HSP) serves as a gain control mechanism at central nervous system (CNS) synapses, including those between the dentate gyrus (DG) and CA3. Improper circuit control of DG\u2010CA3 synapses is hypothesized to underlie epileptogenesis. Here, we sought to (1) identify compounds that preferentially modulate DG\u2010CA3 synapses in primary neuronal culture and (2) determine if these compounds would delay or prevent epileptogenesis in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We previously developed and validated an in vitro assay to visualize the behavior of DG\u2010CA3 synapses and predict functional changes. We used this \u201csynapse\u2010on\u2010chip\u201d assay (quantification of synapse size, number, and type using immunocytochemical markers) to dissect the mechanisms of HSP at DG\u2010CA3 synapses. Using chemogenetic constructs and pharmacological agents we determined the signaling cascades necessary for gain control at DG\u2010CA3 synapses. Finally, we tested the implicated cascades (using kappa opioid receptor (OR) agonists and antagonists) in two models of epileptogenesis: electrical amygdala kindling in the mouse and chemical (pentylenetetrazole) kindling in the rat.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vitro, synapses between DG mossy fibers (MFs) and CA3 neurons are the primary homeostatic responders during sustained periods of activity change. Kappa OR signaling is both necessary and sufficient for the homeostatic elaboration of DG\u2010CA3 synapses, induced by presynaptic DG activity levels. Blocking kappa OR signaling in vivo attenuates the development of seizures in both mouse and rat models of epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study elucidates mechanisms by which synapses between DG granule cells and CA3 pyramidal neurons undergo activity\u2010dependent homeostatic compensation, via OR signaling in vitro. Modulation of kappa OR signaling in vivo alters seizure progression, suggesting that breakdown of homeostatic closed\u2010loop control at DG\u2010CA3 synapses contributes to seizures, and that targeting endogenous homeostatic mechanisms at DG\u2010CA3 synapses may prove useful in combating epileptogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13941","type":"journal-article","created":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T08:50:43Z","timestamp":1510131043000},"page":"106-122","source":"Crossref","is-referenced-by-count":14,"title":["Kappa opioid receptors regulate hippocampal synaptic homeostasis and epileptogenesis"],"prefix":"10.1111","volume":"59","author":[{"given":"Bridget N.","family":"Queenan","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"},{"name":"Interdisciplinary Program in Neuroscience Georgetown University Medical Center Washington DC USA"},{"name":"Department of Mechanical Engineering Neuroscience Research Institute University of California Santa Barbara Santa Barbara CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond L.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"},{"name":"Georgetown Hughes Scholars Program Department of Biology Georgetown University Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor R.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan N.","family":"Huizenga","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Hammack","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Vicini","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"},{"name":"Interdisciplinary Program in Neuroscience Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick A.","family":"Forcelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Physiology Georgetown University Medical Center Washington DC USA"},{"name":"Interdisciplinary Program in Neuroscience Georgetown University Medical Center Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel T. 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