Expression profiling in neuropsychiatric disorders: emphasis on glutamate receptors in bipolar disorder

Abstract

Functional genomics and proteomics approaches are being employed to evaluate gene and encoded protein expression changes with the tacit goal to find novel targets for drug discovery. Genome-wide association studies (GWAS) have attempted to identify valid candidate genes through single nucleotide polymorphism (SNP) analysis. Furthermore, microarray analysis of gene expression in brain regions and discrete cell populations has enabled the simultaneous quantitative assessment of relevant genes. The ability to associate gene expression changes with neuropsychiatric disorders, including bipolar disorder (BP), and their response to therapeutic drugs provides a novel means for pharmacotherapeutic interventions. This review summarizes gene and pathway targets that have been identified in GWAS studies and expression profiling of human postmortem brain in BP, with an emphasis on glutamate receptors (GluRs). Although functional genomic assessment of BP is in its infancy, results to date point towards a dysregulation of GluRs that bear some similarity to schizophrenia (SZ), although the pattern is complex, and likely to be more complementary than overlapping. The importance of single population expression profiling of specific neurons and intrinsic circuits is emphasized, as this approach provides informative gene expression profile data that may be underappreciated in regional studies with admixed neuronal and non-neuronal cell types.

Figure 1

Representative expression profiling of entorhinal stellate neurons (top panel) and regional entorhinal cortex (lower panel) obtained from normal control human postmortem tissue using the Incyte UniGEM V platform. Several genes expressed in stellate cells were also expressed in entorhinal cortex at differing abundance levels (e.g., compare B2, C5, and B10 between the two panels). mRNAs detectable in stellate cells and not in the regional entorhinal cortex dissection was exemplified in G7 and E4. In contrast, several genes present in the entorhinal cortex dissection were below the limit of detection in stellate cells, likely due to the heterogeneity of admixed cell types within the entorhinal cortex (e.g., compared B5, D4, and H10 between panels). Color coded expression levels depict red as high expression and blue as low expression.