Department of Functional Brain Imaging Research, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, 308232, Singapore.
Mol Neurobiol. 2021 Feb;58(2):550-563. doi: 10.1007/s12035-020-02136-5. Epub 2020 Sep 29.
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 F-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.
药理学研究表明，转位蛋白（TSPO）参与调节包括焦虑和抑郁在内的复杂行为，其作用被认为是通过增加神经活性甾体激素的合成来介导的。然而，TSPO 在大脑中的功能仍需通过遗传研究在体内得到证实。为了解决这个问题，我们开发了全局 TSPO 敲除（TSPO-KO）和神经元 TSPO 转基因（TSPO-Tg）小鼠模型，通过高架十字迷宫和强迫游泳试验范式，研究 TSPO 在调节焦虑和抑郁相关行为中的作用。通过质谱法测量大脑中的神经活性甾体激素。使用竞争性正电子发射断层扫描（PET）与 F-FE-DAA1106 研究体内 TSPO 配体药代动力学。遗传 TSPO 缺乏增加焦虑相关行为并损害大脑甾体生成，但不影响抑郁行为。使用 TSPO-KO 模型，我们证明了 Ac-5216（也称为 XBD-173 或 Emapunil）作为一种 TSPO 拮抗剂的特异性，该拮抗剂在竞争性 PET 优化剂量下以高皮质占有率为靶点，具有抗焦虑作用。神经元 TSPO 过表达可降低抑郁行为，该作用依赖于甾体生成，并部分逆转 TSPO-KO 小鼠的焦虑行为。这些发现表明 TSPO 对大脑甾体生成至关重要，并调节焦虑和抑郁相关行为。然而，我们证明了神经元 TSPO 对这些复杂行为的调节作用存在关键差异，这说明了 TSPO 在组织和细胞特异性方面的重要性。TSPO-KO 和 TSPO-Tg 小鼠为开发针对大脑 TSPO 的治疗方法提供了工具和理论依据，以治疗神经精神疾病。
