miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala

Mariusz Mucha (), Anna E. Skrzypiec, Jaison B. Kolenchery, Valentina Brambilla, Satyam Patel, Alberto Labrador-Ramos, Lucja Kudla, Kathryn Murrall, Nathan Skene, Violetta Dymicka-Piekarska, Agata Klejman, Ryszard Przewlocki, Valentina Mosienko () and Robert Pawlak
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Mariusz Mucha: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Anna E. Skrzypiec: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Jaison B. Kolenchery: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Valentina Brambilla: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Satyam Patel: Alberta Health Services
Alberto Labrador-Ramos: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Lucja Kudla: Polish Academy of Sciences
Kathryn Murrall: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Nathan Skene: UK Dementia Research Institute at Imperial College London
Violetta Dymicka-Piekarska: Medical University of Bialystok
Agata Klejman: Polish Academy of Sciences
Ryszard Przewlocki: Polish Academy of Sciences
Valentina Mosienko: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter
Robert Pawlak: University of Exeter Medical School, Department of Clinical and Biomedical Sciences, University of Exeter

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Severe psychological trauma triggers genetic, biochemical and morphological changes in amygdala neurons, which underpin the development of stress-induced behavioural abnormalities, such as high levels of anxiety. miRNAs are small, non-coding RNA fragments that orchestrate complex neuronal responses by simultaneous transcriptional/translational repression of multiple target genes. Here we show that miR-483-5p in the amygdala of male mice counterbalances the structural, functional and behavioural consequences of stress to promote a reduction in anxiety-like behaviour. Upon stress, miR-483-5p is upregulated in the synaptic compartment of amygdala neurons and directly represses three stress-associated genes: Pgap2, Gpx3 and Macf1. Upregulation of miR-483-5p leads to selective contraction of distal parts of the dendritic arbour and conversion of immature filopodia into mature, mushroom-like dendritic spines. Consistent with its role in reducing the stress response, upregulation of miR-483-5p in the basolateral amygdala produces a reduction in anxiety-like behaviour. Stress-induced neuromorphological and behavioural effects of miR-483-5p can be recapitulated by shRNA mediated suppression of Pgap2 and prevented by simultaneous overexpression of miR-483-5p-resistant Pgap2. Our results demonstrate that miR-483-5p is sufficient to confer a reduction in anxiety-like behaviour and point to miR-483-5p-mediated repression of Pgap2 as a critical cellular event offsetting the functional and behavioural consequences of psychological stress.

Date: 2023
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DOI: 10.1038/s41467-023-37688-2

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