title: Positron emission tomography and functional characterization of a complete PBR/TSPO knockout.
abstract: The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer's disease to anxiety. Here we show that global C57BL/6-Tspo(tm1GuWu(GuwiyangWurra))-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from (GuwiyangWurra)TSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of (GuwiyangWurra)TSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.
authors.affiliation: 1] Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia [2] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [4] National Imaging Facility, Sydney, Camperdown, New South Wales 2006, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Banati
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Middleton
authors.affiliation: 1] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [2] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Ronald
authors.initials: R
authors.lastname: Chan
authors.affiliation: 1] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [2] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Claire R
authors.initials: CR
authors.lastname: Hatty
authors.affiliation: 1] Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia [2] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Winnie Wai-Ying
authors.initials: WW
authors.lastname: Kam
authors.affiliation: 1] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [2] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Candice
authors.initials: C
authors.lastname: Quin
authors.affiliation: 1] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [2] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Manuel B
authors.initials: MB
authors.lastname: Graeber
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Arvind
authors.initials: A
authors.lastname: Parmar
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Zahra
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Callaghan
authors.affiliation: Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Fok
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Howell
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Gregoire
authors.affiliation: 1] Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia [2] Centre for Translational Neuroscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Tien
authors.initials: T
authors.lastname: Pham
authors.affiliation: Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Davis
authors.affiliation: 1] Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia [2] Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia [3] Medical Imaging &Radiation Sciences, Faculty of Health Science and Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000311:Adrenal Glands / Q000000981:diagnostic imaging*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000000981:diagnostic imaging*; D002784:Cholesterol / Q000378:metabolism; D005298:Fertility / Q000235:genetics; D007668:Kidney / Q000000981:diagnostic imaging*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011284:Pregnenolone / Q000097:blood; D011524:Protoporphyrins / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics*; D013154:Spleen / Q000000981:diagnostic imaging; D013737:Testis / Q000000981:diagnostic imaging; D051598:Whole Body Imaging
chemical_list: C463819:Bzrp protein, mouse; D011524:Protoporphyrins; D018079:Receptors, GABA; D011284:Pregnenolone; D000255:Adenosine Triphosphate; D002784:Cholesterol; C028025:protoporphyrin IX