Shi Yuan, Cui Mochen, Ochs Katharina, Brendel Matthias, Strübing Felix L, Briel Nils, Eckenweber Florian, Zou Chengyu, Banati Richard B, Liu Guo-Jun, Middleton Ryan J, Rupprecht Rainer, Rudolph Uwe, Zeilhofer Hanns Ulrich, Rammes Gerhard, Herms Jochen, Dorostkar Mario M
Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Nat Neurosci. 2022 Mar;25(3):317-329. doi: 10.1038/s41593-022-01013-9. Epub 2022 Feb 28.
Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.
苯二氮䓬类药物是广泛用于治疗焦虑和失眠的药物。除了产生耐受性和滥用倾向外，长期使用这类药物可能会导致认知障碍并增加患痴呆症的风险。然而，苯二氮䓬类药物可能导致持续性认知衰退的机制尚不清楚。在此，我们报告称，一种广泛使用的苯二氮䓬类药物——地西泮，会损害树突棘的结构可塑性，导致小鼠出现认知障碍。地西泮通过线粒体18 kDa转位蛋白（TSPO）而非经典的A型γ-氨基丁酸受体诱导这些缺陷，这会改变小胶质细胞形态以及对突触物质的吞噬作用。总的来说，我们的研究结果揭示了TSPO配体改变突触可塑性并进而导致认知障碍的一种机制。
