TPH2, hypothalamic–pituitary–adrenal system and environmental adversity

Although converging evidence links exposure to stressful life events with increased risk for disorders of emotion regulation, there is significant individual variability in vulnerability to environmental cues, and the environmentally moderated penetrance of genetic variation is thought to play a major role in determining who will either develop disease or will remain resilient to it [38]. Research on genetic factors in the aetiology of these disorders has been complicated by a mysterious discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations. One explanation for this incongruity is that at least some specific gene effects are conditional on environmental cues, i.e. G × E interaction is present. Numerous studies in rodents reported that environmental adversity including early-life experience (e.g. prenatal stress, maternal neglect/separation) and psychosocial stress throughout the life cycle (e.g. subordinate rank, repeated social defeat) have persistent effects across the lifespan on 5-HT and its metabolite 5-HIAA, as well as on 5-HT receptor subtype expression and function in specific brain regions [136–139]. Studies of G × E interaction using non-human primates and genetically modified mice suggest that particularly adverse early-life experience impact sensitivity to stress-induced alterations in serotonergic neurotransmission later in life [38].

Early work already pointed towards environmental adversity as an important determinant of Tph expression and serotonergic neurotransmission. Acute stress increases Tph (presumably Tph2 isoform) activity in the DR [140] and a stress-induced rise in activity due to phosphorylation of the enzyme has been observed [141]. Inescapable randomly presented sound stress resulted in a transient phosphorylation-dependent rise in enzymatic activity of Tph in the MnR nucleus, whereas chronic sound stress has been shown to induce sustained and phosphatase-resistant increases in Tph activity, providing initial evidence that increases in Tph activity following chronic stress are mediated by increased Tph expression [142]. Repeated immobilization stress leads to increased Tph mRNA and protein concentrations in the DR and MnR nuclei [143]. While stress-mediated changes in Tph mRNA expression following immobilization stress are insensitive to adrenalectomy, chronic dexamethasone treatment of adrenalectomized female and male rats increases Tph mRNA in the pineal gland and decreases Tph mRNA expression in the midbrain raphe complex [144–146].

While it has been reported that Tph2 mRNA is downregulated by synthetic glucocorticoids and modulation of Tph2 expression by long-term antidepressant treatment is dependent on the glucocorticoid status or acute stressors in the murine DR [141,146–150], studies suggest that Tph1 mRNA (which may be present in the DR in extremely small quantities) and Tph protein but not Tph2 mRNA are upregulated by stress, suggesting resistance of the Tph2 isoform expression to stressful stimuli and apparent compensation by Tph1 isoform upregulation [151]. Another meticulously executed study investigated the differential pattern of isoform-specific expression showing that restraint stress for one week induced a 2.5-fold upregulation of Tph1 mRNA in DR with no change in two alternatively spliced Tph2 mRNA species. Therefore, it seems that stress-related mechanisms carry the potential to alter Tph1 and Tph2 mRNA expression, but the increases in Tph2 function may be dependent on the developmental period (e.g. prenatal, adolescence, adulthood), nature and intensity of the cue (e.g. acute, repetitive, chronic), the time course following exposure or context of stressful experience. The recent discovery of alternative splicing in conjunction with RNA editing in the coding region of TPH2 in humans but not in mice adds another level of complexity and demands careful re-examination of previously reported expression data [152].

Although few studies have evaluated the effects of stress-related stimuli on the patterns of gene expression in morpho-functional detail, initial studies support the hypothesis that stress-related stimuli may differentially alter patterns of Tph2 expression in specific subdivisions of the raphe complex, including the DR nucleus, which comprises clusters of neurons with unique cytoarchitectonic characteristics and gene expression patterns. Chronic infusions of the stress- and anxiety-related peptide CRF increased the ratio of Tph2 mRNA expression in the central core region of the dorsal part of the DR, which, among others, extends serotonergic terminals to both the central and basolateral amygdala as well as the medial PFC, whereas Sert mRNA expression was decreased in the midrostrocaudal part of the DR nucleus, which contains many amygdala-projecting neurons [145,153]. In a model of maladaptive stress responsivity, mice deficient in CRF receptor-2 failed to show robust stress-mediated adaptations, including elevations in Tph2 expression and increases in anti-apoptotic factors [154]. Emerging evidence that different subsets of serotonergic neurons project to neural cicuits, which process cognition and emotion and thus integrate physiological responses to environmental cues, will lead to a better understanding of the functional characteristics of specific 5-HT signalling subsystems underlying the pathophysiology of disorders of emotion regulation.

Nevertheless, a role of epigenetic programming in the regulation of Tph2 mRNA expression in specific subdivisions of the rat DR appears likely, and preliminary studies looking at G × E interaction in the non-human primate model have started to provide a useful insight into the neurobiological underpinnings of enhanced Tph2 mRNA and protein expression described in patients with depression, the regional specificity of these effects and their mechanistic consequences. In rhesus monkeys, SNP variants and related haplotypes in both the gene's 5′-flanking transcriptional control region and 3′-UTR with profound in vitro effects on Tph2 expression were demonstrated to influence central 5-HT turnover, HPA axis function and self-injurious behaviour [155,156]. Moreover, investigation of genetic and environmental effects at the Tph2 locus in rhesus monkeys revealed that the functional A2051C polymorphism in rhTph2 is associated with CSF 5-HIAA concentrations, morning plasma cortisol levels and cortisol response to ACTH challenge, whereas the effects on the afternoon cortisol level, plasma ACTH level, dexamethasone suppression of urinary cortisol excretion and aggressive behaviours were dependent on adverse rearing experience.

The neural and molecular mechanisms by which environmental adversity in early life moderates 5-HT system function and thus increases disease risk in adulthood is not known, but may include epigenetic programming of gene expression during (brain) development, which can either be disruptive (maladaptive) or (neuro)plastic in terms of instantly or predictively adaptive [38]. These molecular mechanisms and associated epigenetic markers, such as genome-wide gene expression, DNA methylation, and chromatin modification profiles, are dynamic and reversible and may also provide powerful targets for intervention strategies. Therefore, more insights into the exact role of epigenetic regulation in the process of neurodevelopmental programming contributes to the establishment of early diagnosis and the design of innovative treatments targeting mechanisms of resilience. Together, the results from non-human primate and mouse studies support the G × E interaction hypothesis [38] by showing that allelic variation of Tph2 function is associated with a vulnerability to adversity across the lifespan, leading to multiple unfavourable outcomes resembling emotional disorders. Identifying the molecular mechanisms underlying epigenetic programming by adverse environment in animal models amenable to genetic manipulation or with similar genetic variation is likely to help our understanding of the individual differences in resilience to stress.

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