MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress
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,...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature [academic journals on nature.com]
2024
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| _version_ | 1824459356750479360 |
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| author | Rodrigues, B Leitão, RA Santos, M Trofimov, A Silva, M Inácio, ÂS Abreu, M Nobre, RJ Costa, J Cardoso, AL Milosevic, I Peça, J Oliveiros, B Pereira de Almeida, L Pinheiro, PS Carvalho, AL |
| author_facet | Rodrigues, B Leitão, RA Santos, M Trofimov, A Silva, M Inácio, ÂS Abreu, M Nobre, RJ Costa, J Cardoso, AL Milosevic, I Peça, J Oliveiros, B Pereira de Almeida, L Pinheiro, PS Carvalho, AL |
| author_sort | Rodrigues, B |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2025-02-19T04:40:29Z |
| format | Journal article |
| id | oxford-uuid:7b1bc8d9-b3eb-42c1-b3ba-c7044f85920b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:40:29Z |
| publishDate | 2024 |
| publisher | Springer Nature [academic journals on nature.com] |
| record_format | dspace |
| spelling | oxford-uuid:7b1bc8d9-b3eb-42c1-b3ba-c7044f85920b2025-02-18T20:16:38ZMiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stressJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7b1bc8d9-b3eb-42c1-b3ba-c7044f85920bEnglishJisc Publications RouterSpringer Nature [academic journals on nature.com]2024Rodrigues, BLeitão, RASantos, MTrofimov, ASilva, MInácio, ÂSAbreu, MNobre, RJCosta, JCardoso, ALMilosevic, IPeça, JOliveiros, BPereira de Almeida, LPinheiro, PSCarvalho, ALChronic 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. |
| spellingShingle | Rodrigues, B Leitão, RA Santos, M Trofimov, A Silva, M Inácio, ÂS Abreu, M Nobre, RJ Costa, J Cardoso, AL Milosevic, I Peça, J Oliveiros, B Pereira de Almeida, L Pinheiro, PS Carvalho, AL MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title | MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title_full | MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title_fullStr | MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title_full_unstemmed | MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title_short | MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
| title_sort | mir 186 5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress |
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