| dc.description.abstract | Stress and anxiety disorders are often severely debilitating to the individual and contribute immensely to the health care costs. Surveys have estimated that 33.7% of the population is affected by these disorders at least once in their lifetime. Financial burden of anxiety disorders within the European Union is over 41 billion Euros in 2004. A comprehensive understanding of the underlying neuronal and synaptic plasticity mechanisms that contribute to the adaptation and maladaptation to stress and anxiety is essential to offer therapeutic interventions to stress and anxiety disorders. microRNAs (miRs) have been identified to be involved in the orchestration of cellular mechanisms facilitating neuronal and synaptic plasticity. Animal models have been used to understand these mechanisms since they offer flexibility in studying several aspects of these conditions that are unobtainable from human studies due to technical and ethical issues. Here, we have used mice model to study the role of miRs in the amygdala, a brain region implicated in stress, fear and anxiety. We have identified several miRs, one of which is mir-483-5p, that is upregulated in the amygdala following 6hr restraint stress (6hRS). Further investigation revealed that mir-483-5p is enriched and upregulated in synaptosomes of the amygdalar neurons following stress. Moreover, overexpression of mir-483-5p was sufficient to induce changes in dendritic arborisation and spine proportions. Twelve genes were identified as potential targets of mir-483-5p that are expressed in the amygdala and respond to stress using miR target prediction algorithms and gene ontology lists. Out of these twelve in silico predicted targets, three genes (Pgap2, Gpx3 and Macf1) showed down-regulation by mir-483-5p in N2a cells. Furthermore, using luciferase assay, we established a direct interaction of mir-483-5p at the predicted 3’UTR of these three target mRNAs. In vivo experiments showed that these targets are down-regulated in the amygdala following 6hRS where Pgap2 also showed a reduction in synaptosomal compartments. Finally, we assayed the behaviour of mice after bilaterally overexpressing mir-48-5p or knocking down Pgap2 in mice amygdala. Both of these cohorts of animals, relative to their controls, exhibited anxiolytic behaviour. Hitherto, our data suggest that mir-483- 5p, through the downregulation of Pgap2 in the amygdala, contribute to the mediation of anxiolytic behaviour in mice. Understanding the mechanisms and deciphering the molecular partners of mir-483-5p/Pgap2 interaction could advance our understanding of the mechanisms involved in neuronal and synaptic plasticity leading to anxiolytic behaviour and adaptive response to stress. | en_GB |
