@article{oai:repo.qst.go.jp:00080628,
 author = {Barron, Anna and Higuchi, Makoto and Hattori, Satoko and Kito, Seiji and Suhara, Tetsuya and Ji, Bin and Barron, Anna and Makoto, Higuchi and Satoko, Hattori and Tetsuya, Suhara and Ji, Bin},
 issue = {2},
 journal = {Molecular Neurobiology},
 month = {Sep},
 note = {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-KOmice. 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.},
 pages = {550--563},
 title = {Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons},
 volume = {58},
 year = {2020}
}