Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons
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Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons Anna M. Barron 1,2 & Makoto Higuchi 1 & Satoko Hattori 1 & Seiji Kito 3 & Tetsuya Suhara 1 & Bin Ji 1 Received: 10 June 2020 / Accepted: 17 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Pharmacological studies have implicated the translocator protein (TSPO) in the regulation of complex behaviors including anxiety and depression, effects thought to be mediated by increased synthesis of neuroactive steroid hormones. However, TSPO function in the brain remains to be corroborated in vivo via genetic studies. To address this, we developed global TSPO knockout (TSPO-KO) and neuronal TSPO transgenic (TSPO-Tg) mouse models to investigate TSPO function in the regulation of anxiety- and depression-related behaviors using elevated plus maze and forced swim test paradigms. Neuroactive steroid hormones were measured in the brain by mass spectrometry. In vivo TSPO ligand pharmacokinetics was investigated using competitive PET with 18F-FE-DAA1106. Genetic TSPO deficiency increased anxiety-related behavior and impaired brain steroidogenesis but did not affect depressive behaviors. Using the TSPO-KO model, we then demonstrated the specificity of Ac-5216, also known as XBD-173 or Emapunil, as an anxiolytic targeting TSPO at doses optimized by competitive PET for high cortical occupancy. Neuronal TSPO overexpression decreased depressive behaviors, an effect that was dependent on steroidogenesis, and partially reversed anxiogenic behavior in TSPO-KO mice. These findings demonstrate that TSPO is critical for brain steroidogenesis and modulates anxiety- and depression-related behaviors. However, we demonstrate that key differences in the contribution of neuronal TSPO to the modulation of these complex behaviors, illustrating the tissue- and cell-specific importance of TSPO. The TSPO-KO and TSPO-Tg mice provide the tools and rationale for the development of therapeutic approaches targeting TSPO in the brain for treatment of neuropsychiatric conditions. Keywords Anxiety, . Depression . Neurosteroids . 18-kDa translocator protein (TSPO) . Positron emission tomography
Introduction The translocator protein (TSPO) has been implicated in anxiety- and depression-related neuropsychiatric disorders and identified as a potential target for their diagnosis and treatment [1]. Synthetic ligands of TSPO have been shown to have rapid anxiolytic and anti-depressive effects, with a favorable side effect profile reviewed [1]. Reduced TSPO
* Bin Ji [email protected] 1
Department of Functional Brain Imaging Research, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
2
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore
3
Research, Development and Support Center, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-0024, Japan
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