Written by Charlotte Harrison, Science Writer
Severe or prolonged stress can trigger anxiety disorders, but a lack of knowledge of the underlying mechanisms hampers the discovery of effective treatments. A study in Nature Communications has identified a new genetic pathway – the microRNA (miRNA) miR483-5p acting on its target gene Pgap2 – that curbs the development of stress-related anxiety.
Gene knockdown of this pathway reduced anxiety in a mouse model, suggesting that it might have therapeutic potential.
miRNAs in the amygdala
The researchers focused on miRNAs as these non-coding RNAs are known to spatiotemporally regulate gene expression, making them well-placed to control the pathogenesis of neuropsychiatric disorders. They aimed to identify miRNAs activated selectively by acute psychological stress in the mouse amygdala, a brain area associated with stress.
Acute stress upregulated the expression of five miRNAs, of which miR-483-5p had the highest expression and so was chosen for further studies. In particular, miR-483-5p was upregulated in the synaptic compartment of amygdala neurons, where it repressed the expression of three stress-associated genes — Pgap2, Gpx3 and Macf1 — by binding to 3’UTRs of the mRNAs.
At a neuronal level, upregulation of miR-483-5p caused selective shrinkage of distal dendrites and promoted the formation of mature, mushroom-shaped dendritic spines that are important for formatting, processing and storing emotional memory.
Next, the researchers investigated how miR-483-5p overexpression in the mouse amygdala affects anxiety-like behaviour. Lentiviral overexpression of miR-483-5p increased behaviour typical of low anxiety. Similarly, overexpression of miR-483-5p during acute stress reduced anxiety-like behaviour.
These findings showed that miR-483-5p has a key role in preventing anxiety.
Further work identified Pgap2 as the gene that likely mediates the effects of miR-483-5p; its expression was neuronal, stress-regulated, and could be suppressed by miR-483-5p.
The authors then determined the behavioural effects of Pgap2 suppression. Indeed, mice with reduced Pgap2 expression had decreased anxiety-like behaviour following stress. This result confirmed that the anxiolytic effects of miR-483-5p are caused by the suppression of Pgap2.
Overall, the study identified miR-483-5p as a molecular brake that offsets stress-induced neuronal and behavioural changes.
“We identified and characterised previously unknown molecular events in the [mouse amygdala] that exert an anxiolytic effect. This finding may provide yet unexplored avenues for the development of anxiolytic therapies in humans,” noted the authors.