New tools for measuring the expression of genes on a large scale are now available with oligonucleotide or cDNA microarrays and by proteomic technologies (Avissar & Schreiber, 2002). Advances in genomics and proteomics make it possible to screen very large numbers of candidate genes and proteins. One example of this approach was a study in which methamphetamine-treated rats were used as a model for mania (Niculescu et al., 2000). Gene expression in specific brain regions was compared in treated and untreated animals by oligonucleotide microarrays. Amphetamine administration led to changes in the expression of several genes in rat cortex, and the human homologues of these genes were considered candidates for a role in the pathogenesis of bipolar disorder, including a G-protein coupled receptor kinase (GRK3). This was selected for further examination, as it was mapped to a region of chromosome 22 where linkage to bipolar disorder had previously been reported and weak evidence for association to illness was reported. A parallel approach is to use proteomic technology to survey post-mortem brain material to detect subtle alterations of protein linked to bipolar disorder. In one study, the levels of proteins in the frontal cortex were compared in post-mortem tissue from individuals with bipolar disorder, schizophrenia and depression, and eight protein species displayed disease-specific alterations in the frontal cortex. Positional cloning strategies, microarray methods for genome analysis and proteomic technologies are powerful new methods to identify completely novel pathogenic mechanisms of bipolar disorder.
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