The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse

Abstract

A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from clinical observations that drugs enhancing extracellular levels of 5-HT (5-HT(Ext)) have antidepressant effects in many patients. However, whether such drugs indeed correct a primary deficit remains unresolved. Still, a number of anomalies in putative biomarkers of central 5-HT function have been repeatedly reported in depression patients over the past 40 years, collectively indicating that 5-HT deficiency could be present in depression, particularly in severely ill and/or suicidal patients. This body of literature on putative 5-HT biomarker anomalies and depression has recently been corroborated by data demonstrating that such anomalies indeed occur consequent to severely reduced 5-HT(Ext) levels in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His(439) knockin (Tph2KI) mouse. In this review, we will critically assess the evidence for 5-HT deficiency in depression and the possible role of polymorphisms in the Tph2 gene as a causal factor in 5-HT deficiency, the latter investigated from a clinical as well as preclinical angle.

Figure 1.

Depression-relevant behaviours in Tph2KI mice. (a) (i) Increased tail-suspension immobility (depression-like behaviour, i.e. behavioural despair), (ii) increased latency to cross into lit area in the light-dark box test (anxiety-like behaviour) and (iii) increased male aggression during an encounter with an unknown male in a non-territorial arena (dyadic test) in the Tph2KI (knockin) mice (adapted from Beaulieu et al. [138]). (b) The Tph2KI mice also displayed increased anxiety in the marble burying test (adapted from Jacobsen et al. [83]). Given random access to various dilutions of sweetened condensed milk both WT and Tph2KI mice displayed inverted U-shaped lever-press responses to obtain the reward. (c) However, the Tph2KI mice manifested reduced lever-pressing for sweetened condensed milk, indicating an anhedonic phenotype in this paradigm (previous unpublished data). Filled circles denote knockin, open circles denote WT.

Figure 2.

5-HT biochemical and biomarker profile of Tph2KI mice. (a) 5-HT synthesis, here assessed by 5-HT levels in cell culture, is decreased by approximately 80 per cent in PC12 cells expressing human Tph2 His⁴⁴¹ (R441H) or WT Tph2 (adapted from [104]). (b) (i) 5-HT synthesis as assessed by 5-HTP accumulation, (ii) 5-HT tissue levels and (iii) levels of the primary metabolite 5-HIAA are drastically reduced in the Tph2KI mice carrying the equivalent murine mutation Tph2 His⁴³⁹ to the human Tph2 His⁴⁴¹ (adapted from [138]). (c) Microdialysis data showing reduced frontal cortex diurnal 5-HT_Ext (i) and reduced 5-HT_Ext increases in the Tph2KI mice in response to K depolarization (ii) or SERT blockade with high dose escitalopram (iii) (adapted from [83]). Together, these biochemical findings demonstrate qualitatively and dynamically preserved but quantitatively reduced 5-HT system function in the Tph2KI mice (a,b). (d) (i) Reduced CSF 5-HIAA, (ii) blunted fenfluramine (DexFen)-stimulated plasma prolactin, (iii) blunted 5-HT_1AR agonist(8-OH-DPAT)-induced hypothermia and (iv) increased frontal cortex 5-HT_2ARs in Tph2KI mice (adapted from [83]). This biomarker profile is remarkably similar to findings reported in depression/suicidality.