{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:44:33Z","timestamp":1790019873501,"version":"4.0.1"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"31","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RO1 NS121161"],"award-info":[{"award-number":["RO1 NS121161"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,30]]},"abstract":"<jats:p>\n                    The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest\u2013wake. SCN neurons synthesize and respond to \u03b3-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that \u03b32- and \u03b4-subunits of the GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor in the SCN differ in their regulation of synchrony among circadian cells. We used two approaches: 1) shRNA to knock-down (KD) the expression of either \u03b32 or \u03b4 subunits in the SCN or 2) knock-in mice harboring a point mutation in the M2 domains of the endogenous GABA\n                    <jats:sub>A<\/jats:sub>\n                    \u03b32 or \u03b4 subunits. KD of either \u03b32 or \u03b4 subunits in the SCN increased daytime running and reduced nocturnal running by reducing their circadian amplitude by a third. Similarly, \u03b4 subunit knock-in mice showed decreased circadian amplitude, increased duration of daily activity, and decreased total daily activity. Reduction, or mutation of either \u03b32 or \u03b4 subunits halved the synchrony among, and amplitude of, circadian SCN cells as measured by firing rate or expression of the PERIOD2 protein, in vitro. Surprisingly, overexpression of the \u03b32 subunit rescued these phenotypes following KD or mutation of the \u03b4 subunit, and overexpression of the \u03b4 subunit rescued deficiencies due to \u03b32 subunit KD or mutation. We conclude that \u03b32 and \u03b4 GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor subunits play similar roles in maintaining circadian synchrony in the SCN and amplitude of daily rest\u2013wake rhythms, but that modulation of their relative densities can change the duration and amplitude of daily activities.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2400339121","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T13:38:01Z","timestamp":1721828281000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["GABA\n                    <sub>A<\/sub>\n                    receptor subunit composition regulates circadian rhythms in rest\u2013wake and synchrony among cells in the suprachiasmatic nucleus"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4478-118X","authenticated-orcid":false,"given":"Daniel","family":"Granados-Fuentes","sequence":"first","affiliation":[{"name":"Department of Biology, Washington University in St. Louis, MO 63130-4899"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9427-638X","authenticated-orcid":false,"given":"Peter","family":"Lambert","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University in St. Louis, MO 63130-4899"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-8798","authenticated-orcid":false,"given":"Tatiana","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Biology, Washington University in St. Louis, MO 63130-4899"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0868-0664","authenticated-orcid":false,"given":"Steven","family":"Mennerick","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University in St. Louis, MO 63130-4899"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik D.","family":"Herzog","sequence":"additional","affiliation":[{"name":"Department of Biology, Washington University in St. Louis, MO 63130-4899"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,7,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00965"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021909-135919"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.07.002"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.03.051"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00332.2003"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1992.sp019416"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80876-4"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)90659-J"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90120-A"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00062-9"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s43141-021-00224-0"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207663200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1813"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-04-01350.1997"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.56.1.110"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1625"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(95)00944-L"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(02)00906-5"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)02129-2"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0352-16.2017"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90913-6"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00556.2020"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1996.270.6.C1726"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169-328X(94)00212-W"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00194.2017"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.012743"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420753112"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2021.0454"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2009.06944.x"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52851-w"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0799-18.2018"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP279317"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.00006"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0392-22.2023"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.04.003"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00314.2003"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010168118"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0483-6"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607466103"},{"key":"e_1_3_4_40_2","article-title":"Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus","volume":"120","author":"Patton A.","year":"2023","unstructured":"A. Patton , Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus. Neuroscience. 120, e2301330120 (2023), 10.1073\/pnas.2301330120.","journal-title":"Neuroscience"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1177\/07487304211059770"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/424982"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5750-07.2008"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01078.2003"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521178113"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1419"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04404"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2011.07782.x"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4209-09.2010"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22604"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00119"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-016-2101-z"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.01.036"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11306"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308709101"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0799-18.2018"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52851-w"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6750-6-1"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0377-16.2017"},{"key":"e_1_3_4_60_2","first-page":"103","volume-title":"Circadian Clocks","author":"Maijer B.","year":"2022","unstructured":"B. Maijer, S. Lorensen, A. Finger, H. Herzel, A. Kramer, \u201cSearching novel clock genes using RNAi-based screening\u201d in Circadian Clocks, S. M. Brown, Ed. (SpringerLink US, 2022), pp. 103\u2013114."},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","unstructured":"G. M\u00f6nke F. A. Sorgenfrei C. Schmal A. E. Granada Optimal time frequency analysis for biological data \u2013 pyBOAT. bioRxiv [Preprint] (2020). 10.1101\/2020.04.29.067744 (Accessed 1 May 2020).","DOI":"10.1101\/2020.04.29.067744"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2249-0_3"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw405"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/3708"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.029"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-5193(78)90022-X"},{"key":"e_1_3_4_67_2","unstructured":"D. Granados-Fuentes P. Lambert T. Simon S. Mennerick E. Herzog. Python scripts. Github.com. https:\/\/github.com\/herzog-lab\/daniel-granadosf-et.-al.-2024. Accessed 25 April 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2400339121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T13:38:31Z","timestamp":1721828311000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2400339121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,24]]},"references-count":67,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2024,7,30]]}},"alternative-id":["10.1073\/pnas.2400339121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2400339121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,24]]},"assertion":[{"value":"2024-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2400339121"}}