Work Package 3
microRNAs as regulators of the neuroplasticity of affective disorders
Prof. Dr. Gerhard Schratt
University of Marburg, Institute for Physiological Chemistry
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. It is not known whether they are causally involved in the etiopathology of affective disorders. The aim of this work package is to investigate the contribution of miRNA-regulated gene expression to defective neuroplasticity in affective disorders. To achieve this aim, we plan to pursue the following four main objectives. First, we will identify candidate miRNAs which are differentially expressed in the hippocampus of rat geneenvironment interaction (GxE) models of affective disorders using small RNA deep sequencing. Second, we will investigate the functional relevance of selected miRNAs by gain-and-loss-of function approaches in rats using recombinant adeno-associated virus (rAAV) technology. Several readouts for neuroplasticity will be addressed, including the morphology of dendrites and spines, synapse formation and physiology. Third, we will characterize the downstream signaling pathways regulated by miRNAs involved in affective disorders. Therefore, we will identify biological miRNA targets using a quantitative proteomics approach and perform extensive in silico pathway analysis. Fourth, we will generate small RNA profiles from peripheral blood mononuclear cells of healthy subjects classified by familial genetic and environmental risk factors, in particular the degree of maltreatment. The obtained results will be instrumental for the identification of new small RNA candidates differentially expressed in affective disorder patients and the definition of new affective disorder biotypes. In sum, results from this work package promise to provide first evidence for a causal involvement of impaired miRNA function in affective disorders. Furthermore, data from human subjects will provide a proof of concept for the use of miRNAs as peripheral biomarkers and for therapeutic intervention in patients.