Gene discovery opens new therapeutic avenue for anxiety disorders

As reported by IFL Science, the researchers compared the samples obtained from the stressed mice with those obtained from a control group in order to pinpoint variances in brain activity between these two conditions. They found that miR483-5p, a type of miRNA molecule, was elevated after the stressor was introduced, which in turn repressed a gene called Pgap2.

This gene is believed to play a role in the development of anxiety-related behaviors, and miR483-5p acts as a regulator of this gene, managing the stress response of the amygdala. As a result, the team suspects that this pathway may have a direct role in the manifestation of anxiety symptoms.

A new pathway could offer potential treatment options

The discoveries made by the team could potentially create opportunities for fresh treatment options for individuals who experience anxiety. Although anti-anxiety medications are accessible, their effectiveness is constrained, with less than fifty percent of patients achieving complete recovery upon administration.

Understanding the brain circuitry that leads to anxiety disorders is a priority in combating the condition. The team hopes that the miR483-5p/Pgap2 pathway they identified in this study could provide a new option for the development of anti-anxiety therapies for complex psychiatric conditions in humans. 

"miRNAs are strategically poised to control complex neuropsychiatric conditions such as anxiety. But the molecular and cellular mechanisms they use to regulate stress resilience and susceptibility were until now, largely unknown. The miR483-5p/Pgap2 pathway we identified in this study, activation of which exerts anxiety-reducing effects, offers huge potential for the development of anti-anxiety therapies for complex psychiatric conditions in humans," said Dr. Valentina Mosienko, one of the study's lead authors, in a statement.

The study was published in Nature Communications.

Study 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.