BBB seminar: Vidar M. Steen
Microarray-based global gene expression profiling: A powerful tool to explore brain functions and potential drug targets in psychiatry
Vidar M. Steen
Dr. Einar Martens Research Group for Biological Psychiatry, Section for Medical Genetics and Molecular Medicine and Bergen Mental Health Research Center (BMH), Haukeland University Hospital, University of Bergen; the Norwegian Microarray Consortium (NMC)
DNA microarrays consist of very high numbers of sequence-specific probes that are immobilized onto a surface in a highly parallel, addressable format. This technology allows simultaneous analysis of tens of thousands of different genes or markers in a single experiment, and offers a wide range of potential applications, such as global detection of expression level or genomic copy number from diverse samples. The Norwegian Microarray Consortium (NMC) has for several years collaborated on the establishment of state-of-the-art microarray resources and service for the Norwegian research community.
In this seminar, we will demonstrate how microarray-based gene expression profiling has been used by Dr. Einar Martens Research Group to gain fundamentally new information about (1) brain function and (2) mechanisms of drug action in schizophrenia. 1. In order to improve our understanding of functional consequences of gene expression patterns in the CNS, we generated a global map of differentially expressed genes in selected regions of the adult rat brain (frontomedial-, temporal- and occipital cortex, hippocampus, striatum and cerebellum; both right and left sides) as well as in three major non-neural tissues (spleen, liver and kidney). We identified distinct sets of genes showing significant regional enrichment. Functional annotation of each of these gene sets clearly reflected many important physiological features of the region in question. In addition, we were able to reveal potentially new regional functions. Finally, we have identified a set of ‘CNS-signature' genes that uncover the characteristics of several common neuronal processes in the CNS, with marked over-representation of specific features of synaptic transmission, ion transport and cell communication, as well as numerous novel unclassified genes. 2. We have also performed global gene expression analysis to search for new candidate genes and novel pathways involved in psychotrophic drug action, using cultured human cells exposed to various antipsychotics and antidepressants. We demonstrated that antipsychotic drugs markedly enhance the transcription of a cluster of genes involved in cholesterol- and fatty acid biosynthesis, through activation of the sterol regulatory element-binding protein (SREBP) transcription system. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Our data therefore suggest that drug-induced SREBP-mediated stimulation of cellular lipogenesis represents a therapeutically-relevant mechanism of action in the brain, which may also be important for the metabolic side-effects of antipsychotic drugs, through increased lipid biosynthesis in peripheral tissues. The lecture will present an up-dated overview of these new research areas.