MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress
Rodrigues B. Leitão R.A. Santos M. Trofimov A. Silva M. Inácio Â.S. Abreu M. Nobre R.J. Costa J. Cardoso A.L. Milosevic I. Peça J. Oliveiros B. Pereira de Almeida L. Pinheiro P.S. Carvalho A.L.
March 2025Springer Nature
Molecular Psychiatry
2025#30Issue 31034 - 1046 pp.
Chronic stress exerts profound negative effects on cognitive and emotional behaviours and is a major risk factor for the development of neuropsychiatric disorders. However, the molecular links between chronic stress and its deleterious effects on neuronal and synaptic function remain elusive. Here, using a combination of in vitro and in vivo approaches, we demonstrate that the upregulation of miR-186-5p triggered by chronic stress may be a key mediator of such changes, leading to synaptic dysfunction. Our results show that the expression levels of miR-186-5p are increased both in the prefrontal cortex (PFC) of mice exposed to chronic stress and in cortical neurons chronically exposed to dexamethasone. Additionally, viral overexpression of miR-186-5p in the PFC of naïve mice induces anxiety- and depressive-like behaviours. The upregulation of miR-186-5p through prolonged glucocorticoid receptor activation in vitro, or in a mouse model of chronic stress, differentially affects glutamatergic and GABAergic synaptic transmission, causing an imbalance in excitation/inhibition that leads to altered neuronal network activity. At glutamatergic synapses, we observed both a reduction in synaptic AMPARs and synaptic transmission, whereas GABAergic synaptic transmission was strengthened. These changes could be rescued in vitro by a miR-186-5p inhibitor. Overall, our results establish a novel molecular link between chronic glucocorticoid receptor activation, the upregulation of miR-186-5p and the synaptic changes induced by chronic stress, that may be amenable to therapeutic intervention.
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CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-504, Portugal
CiBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-504, Portugal
Institute for Interdisciplinary Research, University of Coimbra, Coimbra, 3030-789, Portugal
Experimental Biology and Biomedicine Doctoral Programme, Institute for Interdisciplinary Research, University of Coimbra, Coimbra, 3030-789, Portugal
Integrative Brain Function Neurobiology Lab, I.P. Pavlov Department of Physiology, Institute of Experimental Medicine, St. Petersburg, 197022, Russian Federation
Multidisciplinary Institute of Aging, MIA Portugal, University of Coimbra, Coimbra, 3004-504, Portugal
ViraVector, University of Coimbra, Coimbra, 3004-504, Portugal
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, 3000-456, Portugal
iCRB-Coimbra Institute for Clinical and Biomedical Research, University of Coimbra, Coimbra, 3000-548, Portugal
Faculty of Medicine, University of Coimbra, Coimbra, 3000-548, Portugal
Faculty of Pharmacy, University of Coimbra, Coimbra, 3000-548, Portugal
Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Department of Applied Physics and Science for Life Laboratory (SciLifeLab), KTH Royal Institute of Technology, Stockholm, 100 44, Sweden
CNC-Centre for Neuroscience and Cell Biology
CiBB-Center for Innovative Biomedicine and Biotechnology
Institute for Interdisciplinary Research
Experimental Biology and Biomedicine Doctoral Programme
Integrative Brain Function Neurobiology Lab
Multidisciplinary Institute of Aging
ViraVector
Wellcome Centre for Human Genetics
Department of Life Sciences
iCRB-Coimbra Institute for Clinical and Biomedical Research
Faculty of Medicine
Faculty of Pharmacy
Department of Biology
Department of Applied Physics and Science for Life Laboratory (SciLifeLab)
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