Work Package 3
The contribution of environmentally induced global impairments in microRNA biogenesis to the etiology of affective disorders
Prof. Dr. Gerhard Schratt
ETH Zürich, Department of Health, Science and Technology, Institute for Neuroscience, Zurich, Schwitzerland
microRNAs (miRNAs), a large family of small non-coding RNAs, have been demonstrated to control synaptic plasticity in hippocampal neurons in vitro and in vivo. Studies suggest an important pro-resilient function of miRNAdependent gene regulation in various stress-related diseases, including affective disorders (AD). However, it is not known how stressful events (e.g. maltreatment) impair miRNA function to promote depressive behaviour. During the first funding period, we found widespread downregulation of miRNA expression in hippocampal neurons of a rat maltreatment model (juvenile social isolation) using small RNA sequencing, suggesting a global inhibition of miRNA biogenesis in response to maltreatment. This effect was lost in rats heterozygous for the psychiatric risk gene Cacna1c, pointing to perturbed Ca2+-dependent intracellular signalling as a mechanism underlying miRNA dysregulation in maltreated rats. We could identify promising candidate miRNAs for follow-up studies, including the plasticityregulating miR-129-5p.
Within the second funding period, we propose to pursue four different aims to test the hypothesis that impaired Ca2+-dependent miRNA biogenesis at the level of the Dicer1 pre-miRNA processing complex is causally involved in the etiology of endophenotypes of depression in rats and affective disorders in humans. First, we will attempt to characterise modifications of the Dicer1 complex in the rat hippocampus in response to maltreatment. Second, we will try to decipher the signalling pathways that are engaged in neurons of maltreated rats to control miRNA processing activity, with a focus on Ca2+- dependent signalling cascades. The biomaterial for these biochemical and molecular biology experiments will be obtained from the rat geneenvironment (GxE) cohort run in Work Package 2. Third, we plan to restore activity of the Dicer1 complex in the hippocampus of maltreated rats by recombinant viral transgene expression and pharmacological treatment. The necessary intracerebral injection of recombinant adeno-associated virus particles (rAAV) or intraperitoneal injection of pharmacological agents will be done in collaboration with Work Package 2. Fourth, in collaboration with Work Package 5, we will perform an integrative analysis of transcriptome and epigenome signatures of miRNA biogenesis factors based on large-scale longitudinal datasets from AD patients with childhood trauma and available data on course of illness. This extensive expression analysis will be complemented by the identification of rare genetic variants in miRNA biogenesis genes using genome-wide genotyping data of AD cohorts that are available through Work Package 5.
In conclusion, through the execution of highly parallel workflows in the rat model and humans, our project promises to obtain novel insight regarding the function of altered miRNA activity in AD etiology and course of illness. Hence, miRNA biogenesis genes might emerge from this study as novel candidates for biomarkers and treatment strategies.