Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides

Abstract

Deficient levels of serotonin are associated with suicide and depression. Paradoxically, in the dorsal raphe nucleus (DRN) there are more serotonin neurons and more neuronal tryptophan hydroxylase-2 (TPH2) expression postmortem in depressed suicides. In this study, we sought to determine whether greater TPH2 expression in depressed suicides was the result of more TPH2 expression per neuron. In situ hybridization and computer-assisted image analysis were performed on tissue sections throughout the extent of the raphe nuclei at the level of silver grains per neuron to systematically quantify TPH2 neuronal expression. Depressed suicides have 26.5% more TPH2 grain density per neuron in the DRN compared with matched controls (P = 0.04). The difference in grain density is greater at mid-and caudal anatomical levels across the rostrocaudal axis of the DRN. Densitometric analysis of TPH2 expression in the DRN subnuclei showed that higher expression levels were observed at posterior anatomical levels of depressed suicides (121% of control in the caudal subnucleus). Higher TPH2 expression in depressed suicides may explain more TPH2 protein and reflect a homeostatic response to deficient serotonin levels in the brains of depressed suicides. Localized changes in TPH2 expression in specific subnuclei of the DRN suggest that the serotonergic compensatory mechanism in depression and suicide is specifically regulated within the DRN and has implications for regions innervated by this subnucleus.

Probing the diversity of serotonin neurons

“…For instance, the genetic diversity of central serotonin neurons will be interesting to relate to the regionally localized changes in TPH2 expression that have been observed in the raphe of patients with severe depression [108]; at the other extreme, they may help us to understand how abnormal maturation of raphe neurons could be involved in the pathogenesis of sudden infant death syndrome [109]. Another promising direction of research will be the Review.…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Investigation of TPH2 expression in the brainstem of depressed patients who had committed suicide demonstrated increases in TPH2 mRNA [33,34] and protein [35][36][37] within the DR with evidence for specificity in distinct subdivisions. Increased TPH2 expression in depressed patients could result from both rare and frequent variants, their epistatic interaction among themselves (gene-by-gene interaction, G Â G) and their interaction with early life experiences, acute stressful life events or chronic environmental adversity (gene-by-environment interaction, G Â E), all of which can alter 5-HT neurotransmission and have been implicated in determining susceptibility to depression and a spectrum of co-morbid disorders, such as alcohol dependence [38].…”

Disconnect Between Brainstem Serotonin Neurons And Prefrontal Cortex Serotonin Receptors In Suicide

“…We find greater tryptophan hydroxylase 2 protein, the rate-limiting biosynthetic enzyme for 5-HT in brain, in the DRN of depressed suicides [30,31]. Likewise, we find an increase in the amount of TPH2 mRNA expression per neuron as well as the total number of serotonin neurons in depressed suicides [30,32,33]. It is not only an increase in the capacity of the DRN neurons to synthesize 5-HT, we measure more 5-HT and more of the metabolite 5-HIAA [34].…”