Abstract
Affective disorders, such as Major depressive disorder (MDD) and Bipolar disorder (BD), are a group of neuropsychiatric disorders characterized by rofound mood dysregulations. They constitute leading causes of disability and mortality, with especially high rates of suicide. However, the lack of understanding of the molecular mechanisms that trigger the development of affective disorders imposes a challenge to the discovery of novel and effective pharmacotherapies. It is currently accepted that a complex interaction between genetic predisposition and exposure to environmental stressors, such as childhood maltreatment, is required for the development of these disorders. The underlying causes, however, are only poorly understood. One of the main research areas focuses on the dysregulation of synaptic and neural plasticity, based on reports of altered structural and functional brain connectivity in the prefrontal cortex (PFC) and hippocampus of patients. Genes that are involved in neuronal development and plasticity are regulated by microRNAs (miRNAs or miRs), a class of small non-coding RNAs. Importantly, dysregulated miRNA expression is frequently observed in the brain and blood of MDD and BD patients, providing a rationale to consider miRNAs as therapeutic tools and disease biomarkers. This study aimed to investigate how changes in gene expression mediated by miRNAs interact with negative life events, especially during early life, and result in aberrant neuroplastic alterations that increase the susceptibility to affective disorders. For this purpose, I characterized the change in miR-499-5p expression in the blood of affective disorder patients and healthy individuals at higher risk of developing an affective disorder due to a history of childhood maltreatment. I found a significant up-regulation in circulating miR-499-5p in patients and maltreated subjects. Consistently, I observed higher levels of miR-499-5p in the hippocampus of a rat model of early life adversity. To understand how the dysregulation of miR499-5p causes neuronal abnormalities, I used primary cultures from the rat hippocampus to overexpress miR-499-5p and evaluate changes in neuronal morphology and function. In rat hippocampal neurons, miR-499-5p targets the Cacnb2 gene, the auxiliary β-subunit of the L-type Cav1.2 calcium channels, and a risk gene for psychiatric disorders. Elevated miR-499-5p expression inhibited Cacnb2 mRNA translation, impaired dendritic development, and reduced Cav1.2 surface expression and activity. Importantly, overexpression of miR-499-5p in the hippocampus induced short-term memory impairments in the Cacna1c+/- rat model. Based on these results, I propose a mechanism of miRNA-mediated calcium dysfunction in BD susceptibility whereby early life stress induces the expression of miR-499-5p, which in turn impairs dendritic development by inhibiting the expression of an auxiliary subunit of Cav1.2 calcium channels. My work further suggests that the increased blood expression of miR-499-5p could potentially be used as a biomarker of BD development and disease progression.
Martins, Helena Sofia Caria