Project Details
Projekt
MicroRNA Dysfunction in Psychiatric Disorders: Transgenic Rat Models for Schizophrenia Candidate Gene MIR137
Applicant
Professor Dr. Dusan Bartsch
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Biological Psychiatry
Biological Psychiatry
Term
from 2014 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 255059404
This proposal within the framework of the DFG priority programme 1738 Emerging Roles of Non-Coding RNAs in Nervous System Development, Plasticity and Disease studies the role of miR137 in normal and pathologic cognitive functions in the rat brain. MicroRNAs (miRNAs) are small non-protein coding RNAs, which serve as important regulators of post-transcriptional control. Because a single microRNA usually regulates a whole set of genes, disturbances in miRNA-equilibrium can have widespread biological consequences. This is particularly intriguing for highly polygenic diseases like schizophrenia (SCZ) with disturbances in many genes, each contributing only modestly to SCZ pathology. MicroRNA misregulation might therefore constitute a channelling of these effects which combine and amplify the genetic determinants of psychiatric diseases. Recent clinical and experimental evidence strongly implies that miR137 dysfunction may indeed be a central pathway of SCZ pathogenesis. Unfortunately, no suitable animal models are currently available to study miR137 function in the brain. We propose to investigate the biological role of miR137 in normal and pathological cognitive functions in a rat model. We will study the miR137 function by using two new transgenic rat lines which either overexpress miR137 or are deficient of miR137 expression. We will perform an analysis of the genetically modified rats on the molecular, anatomical, electrophysiological and behavioral level. The molecular investigations will comprise, i) characterization of miR137 targets in vivo, ii) analysis of epigenetic alterations in the DNA-methylation signature and iii) analysis of alterations of neurotransmitter content in selected brain regions. On the structural level we characterize dendritic morphology and functionally examine the electrophysiological properties of synapses, as well as population activity. Finally, a comprehensive behavioral analysis is performed to cover major aspects of schizophrenic symptomatology (cognitive, positive and negative symptoms). Our results will contribute to a better understanding of microRNA function (especially miR137) in cells in the brain in vivo and validate and extend the clinical findings implicating miR137 misregulation in SCZ pathology. Advantageously, the use of rats, as a cognitively and socially complex species, provides increased translational value compared to standard mouse models. Further, our models and results may be interesting for other aspects of microRNA function investigated within the SPP 1738, e.g. stem cells, neuronal development and synaptic plasticity or cancer research, where the role of miR137 was implicated as well. The methods applied in our project such as the generation of transgenic rats, the translational mRNA profiling approach (TRAP) and behavioral analysis of genetically modified rodents might be also a valuable add on for other projects within the priority programme 1738.
DFG Programme
Priority Programmes
