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

Author

Listed:
  • Richard B. Banati

    (Life Sciences, Australian Nuclear Science and Technology Organisation
    Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney
    National Imaging Facility, Sydney)

  • Ryan J. Middleton

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Ronald Chan

    (Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney)

  • Claire R. Hatty

    (Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney)

  • Winnie Wai-Ying Kam

    (Life Sciences, Australian Nuclear Science and Technology Organisation
    Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney)

  • Candice Quin

    (Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney)

  • Manuel B. Graeber

    (Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney
    Sydney Medical School, The University of Sydney)

  • Arvind Parmar

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • David Zahra

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Paul Callaghan

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Sandra Fok

    (Brain & Mind Research Institute, The University of Sydney)

  • Nicholas R. Howell

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Marie Gregoire

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Alexander Szabo

    (Life Sciences, Australian Nuclear Science and Technology Organisation
    Centre for Translational Neuroscience, University of Wollongong)

  • Tien Pham

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Emma Davis

    (Life Sciences, Australian Nuclear Science and Technology Organisation)

  • Guo-Jun Liu

    (Life Sciences, Australian Nuclear Science and Technology Organisation
    Brain & Mind Research Institute, The University of Sydney
    Medical Imaging & Radiation Sciences, Faculty of Health Science and Brain & Mind Research Institute, The University of Sydney)

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-Tspotm1GuWu(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 GuwiyangWurraTSPO 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 GuwiyangWurraTSPO 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.

Suggested Citation

  • 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., 2014. "Positron emission tomography and functional characterization of a complete PBR/TSPO knockout," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6452
    DOI: 10.1038/ncomms6452
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