Positron emission tomography and functional characterization of a complete PBR/TSPO knockout

Richard B Banati; Ryan J Middleton; Ronald Chan; Claire R Hatty; Winnie Wai-Ying Kam; Candice Quin; Manuel B Graeber; Arvind Parmar; David Zahra; Paul Callaghan; Sandra Fok; Nicholas R Howell; Marie Gregoire; Alexander Szabo; Tien Pham; Emma Davis; Guo-Jun Liu

doi:10.1038/ncomms6452

Positron emission tomography and functional characterization of a complete PBR/TSPO knockout

Nat Commun. 2014 Nov 19:5:5452. doi: 10.1038/ncomms6452.

Authors

Richard B Banati¹, Ryan J Middleton², Ronald Chan³, Claire R Hatty³, Winnie Wai-Ying Kam⁴, Candice Quin³, Manuel B Graeber⁵, Arvind Parmar², David Zahra², Paul Callaghan², Sandra Fok⁶, Nicholas R Howell², Marie Gregoire², Alexander Szabo⁷, Tien Pham², Emma Davis², Guo-Jun Liu⁴

Affiliations

¹ 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.
² Life Sciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, New South Wales 2232, Australia.
³ 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.
⁴ 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.
⁵ 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.
⁶ Brain &Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
⁷ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Adrenal Glands / diagnostic imaging*
Animals
Behavior, Animal
Brain / diagnostic imaging*
Cholesterol / metabolism
Fertility / genetics
Kidney / diagnostic imaging*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / metabolism*
Positron-Emission Tomography
Pregnenolone / blood
Protoporphyrins / metabolism
Receptors, GABA / genetics*
Spleen / diagnostic imaging
Testis / diagnostic imaging
Whole Body Imaging

Substances

Bzrp protein, mouse
Protoporphyrins
Receptors, GABA
Pregnenolone
Adenosine Triphosphate
Cholesterol
protoporphyrin IX