GABA/GLUTAMATE SIGNALING PATHWAYS IN BIPOLAR AND MAJOR DEPRESSIVE DISORDERS
P.V. Choudary; J.Z. Li; H. Tomita; M. Molnar; S.J. Evans; M.P. Vawter; J.F. Lopez; C.R. Neal; J.D. Stead; R.C. Thompson; R.M. Myers; W.E. Bunney, Jr; H. Akil; S.J. Watson; E.G. Jones
Society for Neuroscience 34th Annual Meeting. 2004.
To understand the pathophysiology of the mood disorders, bipolar affective disorder (BPD) and major depressive disorder (MDD), we have compared gene expression profiles of patients and healthy subjects. Total RNA samples from four different regions, i.e., the anterior cingulate cortex, dorsolateral prefrontal cortex, amygdala and hippocampus, of postmortem brains were each probed with Affymetrix high-density oligonucleotide microarrays. Analysis of duplicate datasets using the probe level model (PLM) showed signal transmission as a prominent biological process with a distinctly altered gene expression pattern. BPD and MDD both showed a trend of upregulation of genes encoding various subunits of GABA receptors and glutamate receptors. Some members of the solute carrier superfamily of genes also showed altered expression levels, indicating impaired small molecule transport and selective neurotransmitter reuptake. The results, together with altered energy metabolism, cell cycle and growth, stress, and apoptosis functions, suggest a possible impairment of GABA and glutamate signaling pathways in mood disorders. Validation of a subset of candidate genes is underway using quantitative real time PCR and in situ hybridization histochemistry analyses. Confirmation of our findings will lend support to the brain-based models of depression, provide insights into the involvement of various regions in mood disorders, and define novel pharmacological targets. Support Contributed By: Pritzker Family Philanthropic Foundation, NIMH Conte Center (P50MH60398), WM Keck Foundation. We thank X. Fan, P. Nguyen, M. Yusufzai, S. Dub and F. Meng for technical help.