Monoamine gene expression in the postmortem human brainstem: effects of age, mood disorders, and suicidality.
R. BERNARD; I. KERMAN; R. C. THOMPSON; E. G. JONES; W. E. BUNNEY; H. AKIL; S. J. WATSON
Society for Neuroscience. 2008.
Serotonin (5-HT) and norepinephrine (NE) are monoaminergic neurotransmitters that modulate cognitive, affective, and homeostatic functions in the CNS. Because patients with mood disorders exhibit pronounced deficits in these functional domains, it is hypothesized that alterations in 5-HT and NE neurotransmission play a major role in the pathophysiology of affective illness. In the present study we sought to determine whether age, major depressive disorder (MDD), bipolar disorder (BPD), or suicidality significantly alter expression of monoaminergic genes in the brainstem nuclei that synthesize 5-HT and NE for release in the forebrain. Experiments were conducted in post-mortem human brain tissue collected from subjects with antemortem diagnoses of MDD (n = 13) or BPD (n = 6) and from psychiatrically-normal control cases (n = 10). Laser capture microdissection was used to selectively harvest tissue from key 5-HT-synthesizing areas - dorsal raphe (DR) and median raphe (MR) nuclei, and from locus coeruleus (LC), a site that contains most of the brain NE neurons. RNA was extracted and processed for gene expression studies using high-density oligonucleotide microarrays and quantitative real-time PCR. Using these methods we monitored the expression of specific monoaminergic RNA transcripts, including synthetic and degradative enzymes, transporters and autoreceptors; expression of select mRNAs was also analyzed by in situ hybridization. Rather than profound across-the-board monoaminergic dysregulation, our results indicate regionally-specific alterations in the expression of select transcripts that regulate 5-HT and NE neurotransmission. Specifically, expression of tryptophan hydroxylase 2 (TPH2) and vesicular monoamine transporter 2 are negatively correlated with age in DR but not MR. In contrast, in the locus coeruleus expression of tyrosine hydroxylase is positively correlated with age. Further analysis of TPH2 expression revealed a strong age-by-diagnosis interaction, so that its expression was significantly upregulated in older (> 50 years old) mood disorder subjects in DR but not MR. TPH2 expression was also upregulated in suicide victims diagnosed with either MDD or BPD as compared to mood disorder subjects that died of other causes. These findings provide further insights into the mechanisms of monoaminergic dysregulation in mood disorders and suicide.