Microarray Analysis of Gene Expression in the Noradrenergic Locus Coeruleus in Major Depression

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Previous studies have demonstrated specific biochemical abnormalities in the noradrenergic locus coeruleus (LC) that are strongly associated with major depressive disorder (MDD). Here, we studied the LC of 4 pairs of MDD and matched control subjects by gene expression microarray analysis in an effort to accelerate the discovery of pathobiological abnormalities of these cells in MDD. Among matching criteria, pH values of control (6.71±0.06) and MDD (6.66±0.12) subjects were closely matched. Gene expression profiling using whole human genome microarrays (Agilent) revealed statistically significant changes in approximately 50 transcripts in the LC of depressive subjects. Quantitative real-time PCR (qPCR) was used to analyze transcripts identified by microarray anlayses. In initial studies of 11 of these transcripts that demonstrated a >2-fold change in microarrays, only 3 transcripts were confirmed by qQPCR in a larger sample of 11-12 pairs of MDD and matched control subjects. Amounts of bone morphogenetic factor-7 (BMP7; p=0.001) and potassium channel subfamily K, member 7 (KCNK7; p=0.049) mRNAs were significantly lower in MDD subjects compared to control subjects (~2-fold difference). In contrast, neurolysin mRNA levels were significantly higher (~3-fold; p=0.03) in MDD than in control subjects. BMP7 is a member of the TGF-β superfamily and has neuroprotective and neurotrophic effects on catecholaminergic neurons. The KCNK family of potassium channels contribute to the excitability of neurons. Neurolysin is a zinc-dependent metallopeptidase involved in neuropeptide metabolism. The present study is the first report of these novel gene expression abnormalities in the LC of MDD subjects. These findings enhance our understanding of the pathobiology of MDD and may represent novel targets for pharmacological management of depression.

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