Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)
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 c...
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| Veröffentlicht in: | Nature neuroscience 2022-03, Vol.25 (3), p.317-329 |
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| creator | 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. |
| description | 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.
Benzodiazepines, used to treat anxiety and sleep disorders, may cause cognitive impairment. Shi et al. demonstrate that this is caused by interaction with the mitochondrial protein TSPO, which drives microglia to excessively remove synapses. |
| doi_str_mv | 10.1038/s41593-022-01013-9 |
| format | Article |
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Benzodiazepines, used to treat anxiety and sleep disorders, may cause cognitive impairment. Shi et al. demonstrate that this is caused by interaction with the mitochondrial protein TSPO, which drives microglia to excessively remove synapses.</description><subject>631/378/2596/1953</subject><subject>631/378/2597/2599</subject><subject>Abuse</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Anxiety</subject><subject>Behavioral Sciences</subject><subject>Benzodiazepines</subject><subject>Benzodiazepines - chemistry</subject><subject>Benzodiazepines - pharmacology</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cognition</subject><subject>Cognitive ability</subject><subject>Dementia disorders</subject><subject>Dendritic plasticity</subject><subject>Dendritic spines</subject><subject>Dendritic structure</subject><subject>Diazepam</subject><subject>Diazepam - pharmacology</subject><subject>Drug development</subject><subject>Drug 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| subjects | 631/378/2596/1953 631/378/2597/2599 Abuse Animal Genetics and Genomics Animals Anxiety Behavioral Sciences Benzodiazepines Benzodiazepines - chemistry Benzodiazepines - pharmacology Biological Techniques Biomedical and Life Sciences Biomedicine Cognition Cognitive ability Dementia disorders Dendritic plasticity Dendritic spines Dendritic structure Diazepam Diazepam - pharmacology Drug development Drug tolerance Impairment Insomnia Liability Mice Microglia Microglia - metabolism Mitochondria Mitochondrial Proteins Neurobiology Neurosciences Phagocytosis Plasticity Proteins Receptors, GABA - metabolism Sleep disorders Spine Synapses Synaptic plasticity γ-Aminobutyric acid |
| title | Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO) |
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