Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons

Pharmacological studies have implicated the translocator protein (TSPO) in the regulation of complex behaviors includinganxiety 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 TSPOknockout (TSPO-KO) and neuronal TSPO transgenic (TSPO-Tg) mouse models to investigate TSPO function in the regulationof anxiety- and depression-related behaviors using elevated plus maze and forced swim test paradigms. Neuroactive steroidhormones were measured in the brain by mass spectrometry. In vivo TSPO ligand pharmacokinetics was investigated usingcompetitive PET with 18F-FE-DAA1106. Genetic TSPO deficiency increased anxiety-related behavior and impaired brainsteroidogenesis but did not affect depressive behaviors. Using the TSPO-KO model, we then demonstrated the specificity ofAc-5216, also known as XBD-173 or Emapunil, as an anxiolytic targeting TSPO at doses optimized by competitive PET for highcortical 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 brainsteroidogenesis and modulates anxiety- and depression-related behaviors. However, we demonstrate that key differences in thecontribution of neuronal TSPO to the modulation of these complex behaviors, illustrating the tissue- and cell-specific importanceof TSPO. The TSPO-KO and TSPO-Tg mice provide the tools and rationale for the development of therapeutic approachestargeting TSPO in the brain for treatment of neuropsychiatric conditions