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Regulation of Anxiety and Depression by Mitochondrial Translocator Protein-Mediated Steroidogenesis: the Role of Neurons
- Source :
- Molecular Neurobiology. 58:550-563
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 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.
- Subjects :
- 0301 basic medicine
Elevated plus maze
Neuroactive steroid
medicine.drug_class
Transgene
Neuroscience (miscellaneous)
Anxiety
Biology
Ligands
Anxiolytic
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Receptors, GABA
medicine
Translocator protein
Animals
Mice, Knockout
Neurons
Behavior, Animal
Depression
Mitochondria
Emapunil
Mice, Inbred C57BL
030104 developmental biology
Neurology
Anxiogenic
Purines
biology.protein
Steroids
Neuroscience
030217 neurology & neurosurgery
Behavioural despair test
Subjects
Details
- ISSN :
- 15591182 and 08937648
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Molecular Neurobiology
- Accession number :
- edsair.doi.dedup.....929710618963f9c66b8c029e4700eb3e