{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:33:57Z","timestamp":1793507637324,"version":"4.5.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01HD100468-01A1"],"award-info":[{"award-number":["1R01HD100468-01A1"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    GABBR1 and GABBR2 are widely expressed in the brain and genetic inhibition of their function leads to neurologic dysfunction and premature death in mice. Given that GABBR1 and GABBR2 heterodimerize to form a functional receptor, global knockout of GABBR1 or GABBR2 results in a similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory and premature death. Both GABBR1 and GABBR2 are expressed in a variety of tissues outside the nervous system and GABA-B receptors have been shown to heterodimerize with other class C GPCRs. However, the neurologic consequences of global GABBR1 or GABBR2 knockout mice have made it difficult to study the effects of loss of GABBR function in other organs. While a conditional knockout for GABBR1 is available, the\n                    <jats:italic>Gabbr2<\/jats:italic>\n                    gene had not been \u201cfloxed\u201d. Therefore, we used CRISPR to insert loxP sites into the\n                    <jats:italic>Gabbr2<\/jats:italic>\n                    locus in mice. These mice are normal at baseline but when bred with mice expressing Cre-recombinase under the control of the ubiquitously expressed Actin gene promoter, Gabbr2\n                    <jats:sup>lox\/lox<\/jats:sup>\n                    mice recapitulate the phenotype of global GABBR2 knockout mice demonstrating alterations throughout the brain, including the cortex, hippocampus and cerebellum. We document abnormal neurological function, increased neuronal cell death, changes in neuronal architecture, and premature death. These mice should be useful tools to study cell type-specific loss of GABBR2 function in the brain and other organs.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0318760","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T18:24:17Z","timestamp":1765823057000},"page":"e0318760","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of a floxed Gabbr2 gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1113-0620","authenticated-orcid":true,"given":"Julie Rose","family":"Hens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Licznerski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4891-1022","authenticated-orcid":true,"given":"Jacqueline","family":"Suarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Jonas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Wysolmerski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"issue":"41","key":"pone.0318760.ref001","doi-asserted-by":"crossref","first-page":"26361","DOI":"10.1074\/jbc.273.41.26361","article-title":"Intracellular retention of recombinant GABAB receptors","volume":"273","author":"A Couve","year":"1998","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0318760.ref002","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0896-6273(00)00012-X","article-title":"A trafficking checkpoint controls GABA(B) receptor heterodimerization","volume":"27","author":"M Margeta-Mitrovic","year":"2000","journal-title":"Neuron"},{"issue":"5","key":"pone.0318760.ref003","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1074\/jbc.M108900200","article-title":"A single subunit (GB2) is required for G-protein activation by the heterodimeric GABA(B) receptor","volume":"277","author":"B Duthey","year":"2002","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0318760.ref004","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0301-0082(95)00012-K","article-title":"A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system","volume":"46","author":"U Misgeld","year":"1995","journal-title":"Prog Neurobiol"},{"issue":"4","key":"pone.0318760.ref005","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1006\/mcne.2000.0908","article-title":"GABAB receptors: a new paradigm in G protein signaling","volume":"16","author":"A Couve","year":"2000","journal-title":"Mol Cell Neurosci"},{"issue":"27","key":"pone.0318760.ref006","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.1523\/JNEUROSCI.5635-03.2004","article-title":"Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice","volume":"24","author":"M Gassmann","year":"2004","journal-title":"J Neurosci"},{"issue":"10","key":"pone.0318760.ref007","doi-asserted-by":"crossref","first-page":"4984","DOI":"10.1210\/en.2007-0653","article-title":"Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes","volume":"148","author":"Z Cheng","year":"2007","journal-title":"Endocrinology"},{"key":"pone.0318760.ref008","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.canlet.2014.03.006","article-title":"GABAergic signaling facilitates breast cancer metastasis by promoting ERK1\/2-dependent phosphorylation","volume":"348","author":"D Zhang","year":"2014","journal-title":"Cancer Lett"},{"issue":"2","key":"pone.0318760.ref009","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.7314\/APJCP.2014.15.2.1041","article-title":"\u03b2-arrestin promotes c-Jun N-terminal kinase mediated apoptosis via a GABA(B)R\u00b7\u03b2-arrestin\u00b7JNK signaling module","volume":"15","author":"J-X Wu","year":"2014","journal-title":"Asian Pac J Cancer Prev"},{"issue":"4","key":"pone.0318760.ref010","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1042\/bst0270530","article-title":"GABA(B) receptors function as heterodimers","volume":"27","author":"FH Marshall","year":"1999","journal-title":"Biochem Soc Trans"},{"key":"pone.0318760.ref011","first-page":"2297","article-title":"GABA(B)-receptor isoforms molecular architecture and distribution","volume":"68","author":"H M\u00f6hler","year":"2001","journal-title":"Life Sci"},{"issue":"34","key":"pone.0318760.ref012","doi-asserted-by":"crossref","first-page":"25030","DOI":"10.1074\/jbc.M700924200","article-title":"Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons","volume":"282","author":"W Chang","year":"2007","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0318760.ref013","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s42255-020-0175-z","article-title":"PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism","volume":"2","author":"W Chang","year":"2020","journal-title":"Nat Metab"},{"issue":"8","key":"pone.0318760.ref014","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1038\/nprot.2014.134","article-title":"Generating genetically modified mice using CRISPR\/Cas-mediated genome engineering","volume":"9","author":"H Yang","year":"2014","journal-title":"Nat Protoc"},{"issue":"6","key":"pone.0318760.ref015","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1161\/CIRCRESAHA.118.314415","article-title":"Specific disruption of Abca1 targeting largely mimics the effects of miR-33 knockout on macrophage cholesterol efflux and atherosclerotic plaque development","volume":"124","author":"NL Price","year":"2019","journal-title":"Circ Res"},{"issue":"1","key":"pone.0318760.ref016","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s13059-017-1220-4","article-title":"Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins","volume":"18","author":"RM Quadros","year":"2017","journal-title":"Genome Biol"},{"key":"pone.0318760.ref017","article-title":"CRISPOR: intuitive guide selection for CRISPR\/Cas9 genome editing experiments and screens","volume":"46","author":"J-P Concordet","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pone.0318760.ref018","volume-title":"Manipulating the mouse embryo: a laboratory manual","author":"A Nagy","year":"2003","edition":"3"},{"issue":"4","key":"pone.0318760.ref019","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods"},{"key":"pone.0318760.ref020","volume-title":"Histotechnology. A self-instructional text","author":"FL Carson","year":"2009","edition":"3"},{"issue":"7","key":"pone.0318760.ref021","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1177\/0192623311422920","article-title":"Neuronal vacuolation","volume":"39","author":"GJ Krinke","year":"2011","journal-title":"Toxicol Pathol"},{"issue":"1","key":"pone.0318760.ref022","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0896-6273(01)00345-2","article-title":"Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1))","volume":"31","author":"V Schuler","year":"2001","journal-title":"Neuron"},{"issue":"6536","key":"pone.0318760.ref023","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/376174a0","article-title":"Hippocampal GABA transporter function in temporal-lobe epilepsy","volume":"376","author":"MJ During","year":"1995","journal-title":"Nature"},{"issue":"1","key":"pone.0318760.ref024","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41593-020-00752-x","article-title":"GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors","volume":"24","author":"S Mederos","year":"2021","journal-title":"Nat Neurosci"},{"issue":"3","key":"pone.0318760.ref025","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0896-6273(00)81069-7","article-title":"GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity","volume":"25","author":"M Scanziani","year":"2000","journal-title":"Neuron"},{"key":"pone.0318760.ref026","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3389\/fneur.2010.00142","article-title":"GABA(B) mediated regulation of sympathetic preganglionic neurons: pre- and postsynaptic sites of action","volume":"1","author":"L Wang","year":"2010","journal-title":"Front Neurol"},{"issue":"5398","key":"pone.0318760.ref027","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1126\/science.283.5398.74","article-title":"Role of heteromer formation in GABAB receptor function","volume":"283","author":"R Kuner","year":"1999","journal-title":"Science"},{"issue":"15","key":"pone.0318760.ref028","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.2174\/0929867323666160406121117","article-title":"Identifying S100B as a biomarker and a therapeutic target for brain injury and multiple diseases","volume":"23","author":"ZZ Chong","year":"2016","journal-title":"Curr Med Chem"},{"key":"pone.0318760.ref029","doi-asserted-by":"crossref","first-page":"1425525","DOI":"10.3389\/fnins.2024.1425525","article-title":"S100B actions on glial and neuronal cells in the developing brain: an overview","volume":"18","author":"K Hern\u00e1ndez-Ortega","year":"2024","journal-title":"Front Neurosci"},{"issue":"6","key":"pone.0318760.ref030","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/sj.npp.1300413","article-title":"Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior","volume":"29","author":"C Mombereau","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"pone.0318760.ref031","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1515\/REVNEURO.2006.17.1-2.111","article-title":"Rearing on hind legs, environmental novelty, and the hippocampal formation","volume":"17","author":"C Lever","year":"2006","journal-title":"Rev Neurosci"},{"key":"pone.0318760.ref032","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbr.2014.04.055","article-title":"Neophobia, NQO1 and SIRT1 as premorbid and prodromal indicators of AD in 3xTg-AD mice","volume":"271","author":"V Torres-Lista","year":"2014","journal-title":"Behav Brain Res"},{"issue":"5","key":"pone.0318760.ref033","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1080\/10253890.2018.1438405","article-title":"Exploratory rearing: a context- and stress-sensitive behavior recorded in the open-field test","volume":"21","author":"O Sturman","year":"2018","journal-title":"Stress"},{"issue":"2","key":"pone.0318760.ref034","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/ana.410170202","article-title":"Antispasticity drugs: mechanisms of action","volume":"17","author":"RA Davidoff","year":"1985","journal-title":"Ann Neurol"},{"issue":"1","key":"pone.0318760.ref035","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1476-5381.1989.tb11780.x","article-title":"Actions of the GABAB agonist, (-)-baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro","volume":"96","author":"CA Allerton","year":"1989","journal-title":"Br J Pharmacol"},{"issue":"1","key":"pone.0318760.ref036","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2045-3701-3-19","article-title":"Development and specification of GABAergic cortical interneurons","volume":"3","author":"C Kelsom","year":"2013","journal-title":"Cell Biosci"},{"key":"pone.0318760.ref037","year":"2024"},{"issue":"11","key":"pone.0318760.ref038","doi-asserted-by":"crossref","first-page":"14780","DOI":"10.1096\/fj.202001561R","article-title":"Deficiency in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through GABABR2-SynCAM1 signaling in chronic migraine rats","volume":"34","author":"X Zeng","year":"2020","journal-title":"FASEB J"},{"issue":"3","key":"pone.0318760.ref039","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1073\/pnas.96.3.1118","article-title":"Glutamate and gamma-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus","volume":"96","author":"KE Vogt","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pone.0318760.ref040","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1002\/ana.410350604","article-title":"The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy","volume":"35","author":"RS Sloviter","year":"1994","journal-title":"Ann Neurol"},{"issue":"2","key":"pone.0318760.ref041","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/00019052-200404000-00013","article-title":"Febrile seizures and mesial temporal sclerosis","volume":"17","author":"F Cendes","year":"2004","journal-title":"Curr Opin Neurol"},{"issue":"3","key":"pone.0318760.ref042","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/jnr.22224","article-title":"Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats","volume":"88","author":"F Yang","year":"2010","journal-title":"J Neurosci Res"},{"key":"pone.0318760.ref043","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fncir.2012.00092","article-title":"The level and distribution of the GABA(B)R1 and GABA(B)R2 receptor subunits in the rat\u2019s inferior colliculus","volume":"6","author":"L Jamal","year":"2012","journal-title":"Front Neural Circuits"},{"key":"pone.0318760.ref044","volume-title":"Histology, Purkinje Cells","author":"MS Paul","year":"2024"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0318760","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T18:24:25Z","timestamp":1765823065000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0318760"}},"subtitle":[],"editor":[{"given":"Yuqing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0318760","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]}}}