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

Animals Benzodiazepines / chemistry Cognition Diazepam / pharmacology Mice Microglia / metabolism Mitochondrial Proteins Receptors, GABA / metabolism

Journal

Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671

Informations de publication

Date de publication:
03 2022
Historique:
received: 29 10 2019
accepted: 14 01 2022
pubmed: 2 3 2022
medline: 27 4 2022
entrez: 1 3 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41593-022-01013-9 PMID: 35228700
pubmed: 35228700
doi: 10.1038/s41593-022-01013-9
pii: 10.1038/s41593-022-01013-9
doi:

Substances chimiques

Bzrp protein, mouse 0
Mitochondrial Proteins 0
Receptors, GABA 0
Benzodiazepines 12794-10-4
Diazepam Q3JTX2Q7TU

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

317-329

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Yuan Shi (Y)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Munich Medical Research School, Ludwig Maximilian University of Munich, Munich, Germany.
ORCID: 0000-0001-6135-1830

Mochen Cui (M)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Medical Research School, Ludwig Maximilian University of Munich, Munich, Germany.

Katharina Ochs (K)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Matthias Brendel (M)

Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.
ORCID: 0000-0002-9247-2843

Felix L Strübing (FL)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
ORCID: 0000-0002-9436-6294

Nils Briel (N)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Medical Research School, Ludwig Maximilian University of Munich, Munich, Germany.
ORCID: 0000-0002-4349-3277

Florian Eckenweber (F)

Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.

Chengyu Zou (C)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.

Richard B Banati (RB)

Australian Nuclear Science and Technology Organisation (ANSTO), Sydney NSW, Australia.
Brain and Mind Centre, Medical Imaging Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney NSW, Australia.
ORCID: 0000-0003-3558-597X

Guo-Jun Liu (GJ)

Australian Nuclear Science and Technology Organisation (ANSTO), Sydney NSW, Australia.
Brain and Mind Centre, Medical Imaging Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney NSW, Australia.
ORCID: 0000-0002-4278-8372

Ryan J Middleton (RJ)

Australian Nuclear Science and Technology Organisation (ANSTO), Sydney NSW, Australia.

Rainer Rupprecht (R)

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Uwe Rudolph (U)

Department of Comparative Biosciences, College of Veterinary Medicine, and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
ORCID: 0000-0001-9396-4746

Hanns Ulrich Zeilhofer (HU)

Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
ORCID: 0000-0001-6954-4629

Gerhard Rammes (G)

Department of Anesthesiology and Intensive Care Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Jochen Herms (J)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany. jochen.herms@dzne.de.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. jochen.herms@dzne.de.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. jochen.herms@dzne.de.
ORCID: 0000-0002-6201-1042

Mario M Dorostkar (MM)

Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany. mario.dorostkar@med.uni-muenchen.de.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. mario.dorostkar@med.uni-muenchen.de.
ORCID: 0000-0001-8037-4907

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Long-term diazepam treatment enhances...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzazépines › Benzodiazépines › Long-term diazepam treatment enhances...
questionsmedicales.fr › Phénomènes psychologiques › Processus mentaux › Cognition › Long-term diazepam treatment enhances...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzazépines › Benzodiazépines › Benzodiazépinones › Diazépam › Long-term diazepam treatment enhances...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Long-term diazepam treatment enhances...
questionsmedicales.fr › Cellules › Névroglie › Microglie › Long-term diazepam treatment enhances...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Long-term diazepam treatment enhances...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs GABA › Long-term diazepam treatment enhances...