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Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia.
Cramer, Teresa; Gill, Raminder; Thirouin, Zahra S; Vaas, Markus; Sampath, Suchita; Martineau, Fanny; Noya, Sara B; Panzanelli, Patrizia; Sudharshan, Tania J J; Colameo, David; Chang, Philip K-Y; Wu, Pei You; Shi, Roy; Barker, Philip A; Brown, Steven A; Paolicelli, Rosa C; Klohs, Jan; McKinney, Rebecca Anne; Tyagarajan, Shiva K.
Affiliation
  • Cramer T; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Gill R; Department of Pharmacology and Therapeutics, McGill University, 3649 Prom. Sir-William-Osler, Montreal, QC H3G 0B1, Canada.
  • Thirouin ZS; Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC H3G1A4, Canada.
  • Vaas M; Clinical Trials Center, University Hospital Zurich, Rämistrasse 100/MOU2, CH 8044 Zürich, Switzerland.
  • Sampath S; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Martineau F; Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, CH 1005 Lausanne, Switzerland.
  • Noya SB; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Panzanelli P; Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.
  • Sudharshan TJJ; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Colameo D; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Chang PK; Department of Pharmacology and Therapeutics, McGill University, 3649 Prom. Sir-William-Osler, Montreal, QC H3G 0B1, Canada.
  • Wu PY; Department of Pharmacology and Therapeutics, McGill University, 3649 Prom. Sir-William-Osler, Montreal, QC H3G 0B1, Canada.
  • Shi R; Department of Pharmacology and Therapeutics, McGill University, 3649 Prom. Sir-William-Osler, Montreal, QC H3G 0B1, Canada.
  • Barker PA; Department of Biology, University of British Columbia, 3187 University Way, ASC 413, Kelowna, BC V1V 1V7, Canada.
  • Brown SA; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
  • Paolicelli RC; Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, CH 1005 Lausanne, Switzerland.
  • Klohs J; Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Wolfgang-Pauli-Strasse 27, CH 8093 Zürich, Switzerland.
  • McKinney RA; Department of Pharmacology and Therapeutics, McGill University, 3649 Prom. Sir-William-Osler, Montreal, QC H3G 0B1, Canada.
  • Tyagarajan SK; Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland.
Sci Adv ; 8(9): eabj0112, 2022 03 04.
Article in En | MEDLINE | ID: mdl-35245123
Microglia interact with neurons to facilitate synapse plasticity; however, signal(s) contributing to microglia activation for synapse elimination in pathology are not fully understood. Here, using in vitro organotypic hippocampal slice cultures and transient middle cerebral artery occlusion (MCAO) in genetically engineered mice in vivo, we report that at 24 hours after ischemia, microglia release brain-derived neurotrophic factor (BDNF) to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the cornu ammonis 1 (CA1) in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75 neurotrophin receptor (p75NTR) and tropomyosin receptor kinase B (TrkB) receptors, respectively. After MCAO, we report that in the peri-infarct area and in the corresponding contralateral hemisphere, similar neuroplasticity occurs through microglia activation and gephyrin phosphorylation at serine-268 and serine-270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point mutations protects against ischemic brain damage, neuroinflammation, and synapse downregulation after MCAO.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Ischemia / Brain-Derived Neurotrophic Factor Limits: Animals Language: En Journal: Sci Adv Year: 2022 Document type: Article Affiliation country: Switzerland Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Ischemia / Brain-Derived Neurotrophic Factor Limits: Animals Language: En Journal: Sci Adv Year: 2022 Document type: Article Affiliation country: Switzerland Country of publication: United States