Glutamate and fibroblast growth factor signaling pathways in locus coeruleus are altered in major depressive disorder (MDD) but not in bipolar disorder (BPD)

R. Bernard; I. A. Kerman; R. C. Thompson; S. Burke; I. Amrein; F. Meng; S. Evans; E. G. Jones; A. F. Schatzberg; J. D. Barchas; W. E. Bunney; R. M. Myers; H. Akil; S. J. Watson
Society for Neuroscience. 2006.


The locus coeruleus (LC) is the major source for noradrenergic innervation of the brain. Dysregulation of noradrenergic neurotransmission is implicated in psychiatric disorders. To study the pathophysiological changes in the LC we used postmortem brains from patients with MDD (N=12), BPD (N=6), and healthy subjects (N=9) to contrast their LC gene expression profiles. All subjects met inclusion criteria of brain pH>6.6 and zero agonal factors. Total RNA samples from laser capture microdissected LC samples were extracted, amplified, and probed with Affymetrix high density oligonucleotide microarrays. Gene expression data were analyzed by ANOVA of robust multichip average algorithm (p=0.1) and by ┬┐mas5calls┬┐ present call algorithm (minimum of 50% presences in one of the 3 health states). Genes meeting these criteria were analyzed using Ingenuity Pathway Analysis (IPA). Compared to healthy individuals, 919 and 409 genes show altered expression in the LC of MDD and BPD patients, respectively. Both disorders have 145 altered genes in common. IPA revealed that 8 genes of the glutamate receptor signaling pathway are significantly altered in MDD (p<0.01) but not in BPD. IPA for MDD showed that the most altered network of 35 genes centers on the fibroblast growth factor system. Validation of candidate genes by quantitative RT-PCR and in situ hybridization is currently ongoing. Confirmation of our results will provide insight into LC specific gene expression changes that occur in MDD and BPD.