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

• Published in: Nature communications 2014-11, Vol.5 (1), p.5452-5452, Article 5452
• Main Authors: Banati, Richard B., Middleton, Ryan J., Chan, Ronald, Hatty, Claire R., Wai-Ying Kam, Winnie, Quin, Candice, Graeber, Manuel B., Parmar, Arvind, Zahra, David, Callaghan, Paul, Fok, Sandra, Howell, Nicholas R., Gregoire, Marie, Szabo, Alexander, Pham, Tien, Davis, Emma, Liu, Guo-Jun
• Format: Article
• Language: English
• Subjects: 13/1; 14; 14/63; 38/77; 38/90; 59; 59/78; 631/1647/245/2092; 631/1647/334/2045; 64/110; 692/308; 82; 82/51; Adenosine Triphosphate - metabolism; Adrenal Glands - diagnostic imaging; Alzheimer's disease; Animals; Behavior, Animal; Benzodiazepines; Brain - diagnostic imaging; Brain research; Cholesterol; Cholesterol - metabolism; Fertility - genetics; Humanities and Social Sciences; Kidney - diagnostic imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; multidisciplinary; Positron-Emission Tomography; Pregnenolone - blood; Proteins; Protoporphyrins - metabolism; Receptors, GABA - genetics; Science; Science (multidisciplinary); Spleen; Spleen - diagnostic imaging; Steroids; Testis - diagnostic imaging; Tomography; Whole Body Imaging
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6452

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. The 18-kDa translocator protein (TSPO) has been implicated in steroid biogenesis and neuroinflammation. Here, the authors create viable and fertile global TSPO knockout mice, challenging the assumption that TSPO is essential for mouse development but suggesting that it may have a role under certain disease conditions.