Age, depression, and suicidality interactions: Effects on the expression of tryptophan hydroxyalase 2 (TPH2), serotonin 1a receptor (HTR1A), and serotonin transporter (SERT) in the human brain.
S. J. WATSON, Jr.; I. A. KERMAN; R. BERNARD; R. C. THOMPSON; E. G. JONES; W. E. BUNNEY; H. AKIL
Society for Neuroscience. 2009.
Serotonin (5-HT) modulates cognitive, affective, and homeostatic functions in the brain. Because depressed individuals exhibit pronounced deficits in these functional domains, it has been hypothesized that alterations in 5-HT neurotransmission play a major role in the pathophysiology of affective illness. In the present study we sought to determine whether age, depression, and suicidality alter expression of genes that regulate 5-HTergic neurotransmission. Experiments were conducted in post-mortem human brain tissue collected from subjects with antemortem diagnoses of major depressive disorder (n = 13) or bipolar disorder (n = 6; depressed at time of death) and from psychiatrically-normal control cases (n = 10). Initial analyses focused on the caudal dorsal raphe (DRc), a key 5-HT-synthesizing region previously implicated in the etiology of depression and suicide. Affymetrix gene expression microarrays and quantitative RT-PCR were used to examine mRNA levels for genes involved in 5-HT synthesis, reuptake, breakdown, and release. In subsequent analyses we used radioactive in situ hybridization to measure expression of TPH2, SERT, and HTR1A in DRc and in the neighboring 5-HT cell groups. Our data demonstrate that: 1) out of nine 5-HTergic genes examined only three - TPH2, HTR1A, and SERT - are influenced by clinical parameters, 2) expression levels of these genes depend on age, clinical state (depression vs. euthymia), and/or suicidality as well as neuroanatomical location, and 3) expression of TPH2 was most sensitive to these variables. TPH2 expression was upregulated in DRc in older (> 50 y.o.), but not younger, depressed patients; in depressed suicides its expression was upregulated, as compared to depressives that did not die from suicide, in: DRc, median raphe, B9 cell group, and in 5-HT cells scattered within the pontine mesencephalic reticular formation. Expression of SERT and HTR1A was likewise increased in depressed suicides, but only in the DRc, and in the case of HTR1A only in older individuals. Taken together these data indicate that depression and suicide have distinct (but partially overlapping) neurobiological underpinnings. DRc appears to be a key region in the regulation of affect, while dysregulation within an extended network of midbrain 5-HT cell groups contributes to suicide. Our animal studies (see Bedrosian, TA, et al. SfN 2009 abstract) indicate that this 5-HT network contributes to aggression and impulsivity, both of which correlate with suicidality. Additional studies are needed to separate the influence of impulsivity and aggression vs. depression on TPH2, HTR1A, and SERT gene expression.