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Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

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 (2022). Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO). Nature Neuroscience, 25(3):317-329.

Abstract

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Language:English
Date:March 2022
Deposited On:31 May 2022 13:41
Last Modified:27 Jan 2025 02:38
Publisher:Nature Publishing Group
ISSN:1097-6256
OA Status:Closed
Publisher DOI:https://doi.org/10.1038/s41593-022-01013-9
PubMed ID:35228700

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