Severe or prolonged stress disrupts brain function and contributes to anxiety disorders. The amygdala, a region involved in emotional processing, plays a crucial role in stress-induced anxiety. MicroRNAs (miRNAs) are small RNA sequences that regulate gene expression and are implicated in some neuropsychiatric conditions, including anxiety. However, the specific role of miRNAs in the amygdala and their effects on stress remain poorly understood. In a novel study, a team of researchers at University of Exeter Medical School supervised by Professor Robert Pawlak uncovered the remarkable role of the miRNA miR-483-5p, in offsetting the functional and behavioural effects of stress in male mice – utilising custom lentiviral particles from AMSBIO.
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April 26, 2023Exploring miR-483-5p in the Amygdala
Under psychological stress, gene expression in the amygdala undergoes significant changes, partly regulated by miRNAs. Following acute restraint stress, miR-483-5p was found to show the highest upregulation out of five identified miRNAs in the amygdala. Using fluorescence in situ hybridization (FISH) analysis, Prof. Pawlak and his team revealed that miR-483-5p is mainly expressed in the neuronal component of the amygdala, particularly within the synaptic compartment. Furthermore, stress was found to increases its expression in synaptosomes. These findings suggest that miR-483-5p is enriched in the synaptic compartment and locally regulated by stress.
Following bioinformatic analysis, the team identified twelve genes that could be targets of miR-483-5p. In vitro and in situ neuronal experiments confirmed that miR-483-5p suppresses the expression of specific target genes, including Pgap2, Gpx3, and Macf1, which was confirmed further through luciferase assays. Pgap2 emerged as a primary target for subsequent behavioural experiments due to its potential role in mediating the effects of miR-483-5p in the amygdala.
Impact on Neuronal Morphology
Prof. Pawlak and his fellow researchers found that miR-483-5p causes selective shrinkage of distal dendrites of amygdala neurons, while proximal dendrites remain unchanged. Additionally, miR-483-5p triggers changes in dendritic spine morphology, leading to an increase in mature mushroom spines and a decrease in neuroplastic filopodia-like structures. These observations were supported by similar findings in mice injected with lentiviral particles expressing miR-483-5p in the amygdala. A small increase in spinal density was also noted in in situ neurons overexpressing miR-483-5p. These results indicate that miR-483-5p promotes the maturation of mushroom-like spines and increases spine density following psychological stress.
Anxiolytic Effects Mediated by Pgap2 Suppression
In mice, lentiviral overexpression of miR-483-5p in the amygdala reduced anxiety levels and promoted exploration of open arms in a maze, indicating an anxiolytic effect. Additionally, overexpression of miR-483-5p prevented the development of anxiety-like behaviour in mice exposed to acute restraint stress. Suppression of the Pgap2 gene was achieved using custom lentiviral particles and controls made by AMSBIO. Similarly, Pgap2 suppression resulted in decreased anxiety-like behaviour and increased exploration of the maze. Co-overexpression of miR-483-5p and miR-483-5p-resistant Pgap2 effectively counteracted the anxiolytic effects of miR-483-5p, highlighting the crucial role of miR-483-5p-mediated repression of Pgap2.
Conclusion
The findings made by the researchers at the University of Exeter Medical School shed light on the role of miR-483-5p in attenuating the detrimental effects of stress on brain function and anxiety-related behaviours in male mice. These insights contribute to a deeper understanding of the complex interplay between miRNAs, stress, and anxiety, opening potential avenues for future therapeutic interventions.
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Further reading
Mucha, M., Skrzypiec, A.E., Kolenchery, J.B. et al. Nat Commun 14, 2134 (2023). https://doi.org/10.1038/s41467-023-37688-2
