TY - JOUR
T1 - Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis
T2 - the Role of Neurons
AU - Barron, Anna M.
AU - Higuchi, Makoto
AU - Hattori, Satoko
AU - Kito, Seiji
AU - Suhara, Tetsuya
AU - Ji, Bin
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Japan Advanced Molecular Imaging Program, Strategic Research Program for Brain Sciences (Integrated Research on Neuropsychiatric Disorders); JSPS KAKENHI Scientific Research on Innovative Areas (“Brain Environment”) Grant Number 23111009 to M.H.; JSPS KAKENHI (Young Scientists) Grant Number 26830038 to A.M.B.; and the Brain Mapping by Integrated Neurotechnologies for Disease Studies (14533254) to M.H., from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Nanyang Assistant Professorship from Nanyang Technological University Singapore (to A.M.B.).
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
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U2 - 10.1007/s12035-020-02136-5
DO - 10.1007/s12035-020-02136-5
M3 - Article
AN - SCOPUS:85091680700
VL - 58
SP - 550
EP - 563
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 2
ER -