{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:16:02Z","timestamp":1791177362587,"version":"4.1.0"},"reference-count":62,"publisher":"Society for Neuroscience","issue":"9","license":[{"start":{"date-parts":[[2007,8,28]],"date-time":"2007-08-28T00:00:00Z","timestamp":1188259200000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2007,2,28]]},"abstract":"<jats:p>Recently, we demonstrated cyclic alterations in GABA<jats:sub>A<\/jats:sub>receptor (GABA<jats:sub>A<\/jats:sub>R) subunit composition over the ovarian cycle correlated with fluctuations in progesterone levels. However, it remains unclear whether this physiological regulation of GABA<jats:sub>A<\/jats:sub>Rs is directly mediated by hormones. Here, we show that both ovarian and stress hormones are capable of reorganizing GABA<jats:sub>A<\/jats:sub>Rs by actions through neurosteroid metabolites. The cyclic alterations in GABA<jats:sub>A<\/jats:sub>Rs demonstrated in female mice can be mimicked with exogenous progesterone treatment in males or in ovariectomized females. Progesterone (5 mg\/kg, twice daily) upregulates the expression of GABA<jats:sub>A<\/jats:sub>R \u03b4 subunits and enhances the tonic inhibition mediated by these receptors in dentate gyrus granule cells (DGGCs). These changes in males as well as ovarian cycle-induced changes in females can be blocked by finasteride, an antagonist of neurosteroid synthesis from progesterone. The altered GABA<jats:sub>A<\/jats:sub>R expression is unaffected by the progesterone receptor antagonist RU486 [mifepristone (11\u03b2-[<jats:italic>p<\/jats:italic>-(dimethylamino)phenyl]-17\u03b2-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], suggesting that neurosteroid synthesis and not progesterone receptor activation underlies the hormone-mediated effects on GABA<jats:sub>A<\/jats:sub>R expression. Neurosteroids can alter GABA<jats:sub>A<\/jats:sub>R expression on a rapid timescale, because GABA<jats:sub>A<\/jats:sub>R upregulation can be induced in brain slices maintained<jats:italic>in vitro<\/jats:italic>after a short (30 min) treatment with the neurosteroid 3\u03b1,5\u03b1-tetrahydrodeoxycorticosterone (THDOC) (100 n<jats:sc>m<\/jats:sc>). Consistent with these rapid alterations, acute stress, a condition known to quickly raise THDOC levels, within 30 min induces upregulation of GABA<jats:sub>A<\/jats:sub>R \u03b4 subunit expression and increase tonic inhibition in DGGCs. These results reveal that several physiological conditions characterized by elevations in neurosteroid levels induce a reorganization of GABA<jats:sub>A<\/jats:sub>Rs through the action of neurosteroids.<\/jats:p>","DOI":"10.1523\/jneurosci.4945-06.2007","type":"journal-article","created":{"date-parts":[[2007,2,28]],"date-time":"2007-02-28T19:54:48Z","timestamp":1172692488000},"page":"2155-2162","source":"Crossref","is-referenced-by-count":215,"title":["Neurosteroid Synthesis-Mediated Regulation of GABA<sub>A<\/sub>Receptors: Relevance to the Ovarian Cycle and Stress"],"prefix":"10.1523","volume":"27","author":[{"given":"Jamie","family":"Maguire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Mody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2007,2,28]]},"reference":[{"key":"2023041303234351000_27.9.2155.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606544103"},{"key":"2023041303234351000_27.9.2155.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1993.tb07472.x"},{"key":"2023041303234351000_27.9.2155.3","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(94)90123-6"},{"key":"2023041303234351000_27.9.2155.4","doi-asserted-by":"publisher","DOI":"10.1159\/000126953"},{"key":"2023041303234351000_27.9.2155.5","doi-asserted-by":"publisher","DOI":"10.1016\/0091-3057(95)02133-7"},{"key":"2023041303234351000_27.9.2155.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7742(01)46065-X"},{"key":"2023041303234351000_27.9.2155.7","doi-asserted-by":"publisher","DOI":"10.2174\/1381612023396681"},{"key":"2023041303234351000_27.9.2155.8","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1703"},{"key":"2023041303234351000_27.9.2155.9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601309"},{"key":"2023041303234351000_27.9.2155.10","first-page":"103","article-title":"Effects of tamoxifen, mifepristone and cyproterone on the electroconvulsive threshold and pentetrazole-induced convulsions in mice","volume":"54","author":"Borowicz","year":"2002","journal-title":"Pol J Pharmacol"},{"key":"2023041303234351000_27.9.2155.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004910200"},{"key":"2023041303234351000_27.9.2155.12","first-page":"102","article-title":"GABAA receptor function is modulated via multiple interactions with both protein kinases and kinase anchoring proteins","volume":"78","author":"Brandon","year":"2001","journal-title":"J Neurochem"},{"key":"2023041303234351000_27.9.2155.13","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1286.003"},{"key":"2023041303234351000_27.9.2155.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.050424697"},{"key":"2023041303234351000_27.9.2155.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2004.03.022"},{"key":"2023041303234351000_27.9.2155.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13284"},{"key":"2023041303234351000_27.9.2155.17","doi-asserted-by":"publisher","DOI":"10.1038\/2798"},{"key":"2023041303234351000_27.9.2155.18","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1523\/JNEUROSCI.20-09-03067.2000","article-title":"Neurosteroid modulation of GABA IPSCs is phosphorylation dependent","volume":"20","author":"Fancsik","year":"2000","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.19","doi-asserted-by":"publisher","DOI":"10.1210\/en.138.7.2763"},{"key":"2023041303234351000_27.9.2155.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1499-1654.2000.001534.x"},{"key":"2023041303234351000_27.9.2155.21","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1523\/JNEUROSCI.10-04-01286.1990","article-title":"Gonadal-steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood","volume":"10","author":"Gould","year":"1990","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.22","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20540"},{"key":"2023041303234351000_27.9.2155.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.08.013"},{"key":"2023041303234351000_27.9.2155.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(03)00251-X"},{"key":"2023041303234351000_27.9.2155.25","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10508"},{"key":"2023041303234351000_27.9.2155.26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215903"},{"key":"2023041303234351000_27.9.2155.27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1159\/000121891","article-title":"Biosynthesis of ovarian steroids in the rabbit: influence of progesterone or estradiol implantation into the hypothalamus and limbic structures","volume":"5","author":"Kawakami","year":"1969","journal-title":"Neuroendocrinology"},{"key":"2023041303234351000_27.9.2155.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-4388(03)00064-3"},{"key":"2023041303234351000_27.9.2155.29","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0022-3565(24)38006-1","article-title":"Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice","volume":"288","author":"Kokate","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"2023041303234351000_27.9.2155.30","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.63.9.957"},{"key":"2023041303234351000_27.9.2155.31","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(91)90167-4"},{"key":"2023041303234351000_27.9.2155.32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R300024200"},{"key":"2023041303234351000_27.9.2155.33","doi-asserted-by":"publisher","DOI":"10.1038\/nn1469"},{"key":"2023041303234351000_27.9.2155.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0193-953X(01)00009-0"},{"key":"2023041303234351000_27.9.2155.35","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1152\/jn.2002.87.5.2624","article-title":"Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells","volume":"87","author":"Nusser","year":"2002","journal-title":"J Neurophysiol"},{"key":"2023041303234351000_27.9.2155.36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0169-328X(95)00118-C","article-title":"Chronic exposure to stress levels of corticosterone alters GABAA receptor subunit mRNA levels in rat hippocampus","volume":"34","author":"Orchinik","year":"1995","journal-title":"Brain Res Mol Brain Res"},{"key":"2023041303234351000_27.9.2155.37","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-1211(00)00194-7"},{"key":"2023041303234351000_27.9.2155.38","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.molbrainres.2004.10.047","article-title":"Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons","volume":"138","author":"Pierson","year":"2005","journal-title":"Brain Res Mol Brain Res"},{"key":"2023041303234351000_27.9.2155.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.10.4553"},{"key":"2023041303234351000_27.9.2155.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(03)00023-3"},{"key":"2023041303234351000_27.9.2155.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.10.016"},{"key":"2023041303234351000_27.9.2155.42","doi-asserted-by":"crossref","first-page":"3795","DOI":"10.1523\/JNEUROSCI.22-09-03795.2002","article-title":"Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility","volume":"22","author":"Reddy","year":"2002","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.43","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)90692-5"},{"key":"2023041303234351000_27.9.2155.44","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0750732.x"},{"key":"2023041303234351000_27.9.2155.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2005.04.026"},{"key":"2023041303234351000_27.9.2155.46","doi-asserted-by":"publisher","DOI":"10.1210\/mend-5-3-424"},{"key":"2023041303234351000_27.9.2155.47","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(81)90524-2"},{"key":"2023041303234351000_27.9.2155.48","doi-asserted-by":"crossref","first-page":"RC223","DOI":"10.1523\/JNEUROSCI.22-10-j0003.2002","article-title":"Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons","volume":"22","author":"Stell","year":"2002","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2435457100"},{"key":"2023041303234351000_27.9.2155.50","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.24.1.299"},{"key":"2023041303234351000_27.9.2155.51","doi-asserted-by":"publisher","DOI":"10.1038\/nn888"},{"key":"2023041303234351000_27.9.2155.52","doi-asserted-by":"publisher","DOI":"10.1210\/endo-83-2-207"},{"key":"2023041303234351000_27.9.2155.53","doi-asserted-by":"publisher","DOI":"10.1126\/science.7190730"},{"key":"2023041303234351000_27.9.2155.54","doi-asserted-by":"crossref","first-page":"10650","DOI":"10.1523\/JNEUROSCI.23-33-10650.2003","article-title":"Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus","volume":"23","author":"Wei","year":"2003","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.55","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2040-04.2004"},{"key":"2023041303234351000_27.9.2155.56","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0169-328X(95)00087-9","article-title":"Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus","volume":"32","author":"Weiland","year":"1995","journal-title":"Brain Res Mol Brain Res"},{"key":"2023041303234351000_27.9.2155.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(97)00110-0"},{"key":"2023041303234351000_27.9.2155.58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.2000.tb00203.x"},{"key":"2023041303234351000_27.9.2155.59","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1523\/JNEUROSCI.12-07-02549.1992","article-title":"Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat","volume":"12","author":"Woolley","year":"1992","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.60","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903360210"},{"key":"2023041303234351000_27.9.2155.61","doi-asserted-by":"crossref","first-page":"7680","DOI":"10.1523\/JNEUROSCI.14-12-07680.1994","article-title":"Estradiol regulates hippocampal dendritic spine density via an N-methyl-d-aspartate receptor-dependent mechanism","volume":"14","author":"Woolley","year":"1994","journal-title":"J Neurosci"},{"key":"2023041303234351000_27.9.2155.62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.6.3204"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.4945-06.2007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T10:51:51Z","timestamp":1736851911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.4945-06.2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,2,28]]},"references-count":62,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2007,2,28]]},"published-print":{"date-parts":[[2007,2,28]]}},"alternative-id":["10.1523\/JNEUROSCI.4945-06.2007"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.4945-06.2007","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,2,28]]}}}