Abstract

Gastrin releasing peptide (GRP) and glucocorticoid-induced receptor (GIR) mRNA expression are upregulated in locus coeruleus of bipolar disorder (BPD) but not in major depressive disorder (MDD) patients

R. BERNARD; I. A. KERMAN; R. C. THOMPSON; S. M. BURKE; S. J. EVANS; F. MENG; E. G. JONES; W. E. BUNNEY; R. M. MYERS; A. F. SCHATZBERG; J. D. BARCHAS; H. AKIL; S. J. WATSON
Society for Neuroscience. 2007.

The locus coeruleus (LC) is the major source for noradrenergic innervation of the brain. Dysregulation of noradrenergic neurotransmission has been implicated in psychiatric disorders. To understand the pathophysiological changes that occur in the LC we have used postmortem brains of patients with BPD (N=6), MDD (N=12) and psychiatrically-normal control subjects (N=9) to contrast their LC gene expression profiles. Total RNA samples from laser capture microdissected LC samples were amplified and probed with Affymetrix oligonucleotide microarrays. Gene expression data were analyzed by ANOVA of the robust multichip average algorithm and by the MAS5calls present call algorithm. Inclusion criteria for altered MDD or BRD gene expression were set at p = 0.05 and a minimum of 50% present in control, MDD, or BPD group. Genes meeting these criteria were filtered for a disease specific fold change of = 30%. For BPD 13 genes met these criteria and 3 of them were subjected to confirmation by quantitative real time polymerase chain reaction (qRT-PCR). RT-PCR results were evaluated using Student t-test comparing cycle thresholds (Ct) between control and disease group subjects for each tested transcript. Probes for GRP (p=0.04) and GIR (p=0.03) showed statistically significant decreases in cycle threshold (Ct) in BPD subjects indicating significant upregulation and confirming microarray results. Neuropeptide Y mRNA was upregulated in BPD by microarray but showed no difference in Ct by qRT-PCR. In MDD none of the three transcripts showed altered microarray or qRT-PCR results. Validation of the two altered BPD genes by in situ hybridization is currently ongoing. Elevated GRP immunoreactivity in the LC of suicide victims has been reported, implicating GRP in the etiology of psychiatric disorders. Upregulated GIR mRNA in the prefrontal cortex has been reported during behavioral sensitization to amphetamine, suggesting a role of GIR in drug reward. The present study is the first using LCM on p ostmortem human nuclei in combination with gene expression microarrays and qRT-PCR showing elevated gene expression of GRP and GIR in locus coeruleus of BPD but not MDD patients. Several of the authors are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. A shared intellectual property agreement exists between this philanthropic fund and the University of Michigan, Stanford University, the Weill Medical College of Cornell University, the Universities of California at Davis, and at Irvine, to encourage the development of appropriate findings for research and clinical applications.