{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:45:47Z","timestamp":1790707547109,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,10,13]],"date-time":"2016-10-13T00:00:00Z","timestamp":1476316800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004963","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["602531"],"award-info":[{"award-number":["602531"]}],"id":[{"id":"10.13039\/501100004963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2013 0879"],"award-info":[{"award-number":["2013 0879"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The inhibition of glycolysis exerts potent antiseizure effects, as demonstrated by the efficacy of ketogenic and low\u2010glucose\/nonketogenic diets in the treatment of drug\u2010resistant epilepsy. <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010sensitive potassium (K<jats:sub>ATP<\/jats:sub>) channels have been initially identified as the main determinant of the reduction of neuronal hyperexcitability. However, a plethora of other mechanisms have been proposed. Herein, we report the ability of 2\u2010deoxy\u2010<jats:sc>d<\/jats:sc>\u2010glucose (2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content>), a glucose analog that inhibits glycolytic enzymes, of potentiating \u03b3\u2010aminobutyric acid (<jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>)ergic tonic inhibition via neurosteroid\u2010mediated activation of extrasynaptic <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content><jats:sub>A<\/jats:sub> receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Acute effects of 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content> on the <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010sensitive potassium currents, <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic tonic inhibition, firing activity, and interictal events were assessed in hippocampal slices by whole\u2010cell patch\u2010clamp and local field potential recordings of dentate gyrus granule cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Acute application of 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content> activates two distinct outward conductances: a K<jats:sub>ATP<\/jats:sub> channel\u2013mediated current and a bicuculline\u2010sensitive tonic current. The effect of 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content> on such <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic tonic currents was fully prevented by either finasteride or <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>11195, which are specific inhibitors of the neurosteroidogenesis pathway acting via different mechanisms. Moreover, the oxidized form of vitamin C, dehydroascorbic acid, known for its ability to induce neurosteroidogenesis, also activated a bicuculline\u2010sensitive tonic current in a manner indistinguishable from that of 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content>. Finally, we found that the enhancement of K<jats:sub>ATP<\/jats:sub> current by 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content> primarily regulates intrinsic firing rate of granule cells, whereas the increase of the <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic tonic current plays a key role in reducing the frequency of interictal events evoked by treatment of hippocampal slices with the convulsive agent 4\u2010aminopyridine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>We demonstrated, for the first time, that 2\u2010<jats:styled-content style=\"fixed-case\">DG<\/jats:styled-content> potentiates the extrasynaptic tonic <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic current through activation of neurosteroidogenesis. Such tonic inhibition represents the main conductance responsible for the antiseizure action of this glycolytic inhibitor.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13578","type":"journal-article","created":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T01:12:17Z","timestamp":1476407537000},"page":"1987-2000","source":"Crossref","is-referenced-by-count":40,"title":["2\u2010Deoxy\u2010<scp>d<\/scp>\u2010glucose enhances tonic inhibition through the neurosteroid\u2010mediated activation of extrasynaptic <scp>GABA<\/scp><sub>A<\/sub> receptors"],"prefix":"10.1111","volume":"57","author":[{"given":"Nicola","family":"Forte","sequence":"first","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology Istituto Italiano di Tecnologia Genova Italy"},{"name":"Department of Experimental Medicine University of Genova Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucian","family":"Medrihan","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology Istituto Italiano di Tecnologia Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Cappetti","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology Istituto Italiano di Tecnologia Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Baldelli","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology Istituto Italiano di Tecnologia Genova Italy"},{"name":"Department of Experimental Medicine University of Genova Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Benfenati","sequence":"additional","affiliation":[{"name":"Center for Synaptic Neuroscience and Technology Istituto Italiano di Tecnologia Genova Italy"},{"name":"Department of Experimental Medicine University of Genova Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,10,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.108.4.898"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.57002.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb01589.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410030410"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-197605000-00006"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000187071.24292.9e"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1791"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3163-07.2007"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21603"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)64988-9"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.10.5321"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25868"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2013.2299"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1881"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.11.005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00373983"},{"key":"e_1_2_8_18_1","first-page":"368","article-title":"2\u2010Deoxy\u2010d\u2010glucose\u2010induced changes in membrane potential, input resistance, and excitatory postsynaptic potentials of CA1 hippocampal neurons","volume":"75","author":"Zhao YT","year":"1997","journal-title":"Can J Physiol Pharmacol"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1357-14.2014"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04711"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19990701)57:1<48::AID-JNR6>3.0.CO;2-L"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02593.x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00115"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2435457100"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.032"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1997.785ba.x"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1625"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1009"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4642-03.2004"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2010.08.009"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2007.02.008"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.09.001"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20899"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2002.87.5.2624"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606544103"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2003.12.023"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)02269-6"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2014.02.016"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12663"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1998.71031108.x"},{"key":"e_1_2_8_41_1","first-page":"327","article-title":"Cell\u2010type specific expression of ATP\u2010sensitive potassium channels in the rat hippocampus","volume":"514","author":"Zawar C","year":"1999","journal-title":"J Physiol"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.13578","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.13578","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.13578","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T13:58:55Z","timestamp":1695736735000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.13578"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,13]]},"references-count":40,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1111\/epi.13578"],"URL":"https:\/\/doi.org\/10.1111\/epi.13578","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,13]]}}}