Affinage

TPH2

Tryptophan 5-hydroxylase 2 · UniProt Q8IWU9

Length
490 aa
Mass
56.1 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TPH2 is the brain-specific isoform of tryptophan hydroxylase that catalyzes the rate-limiting step of serotonin biosynthesis, and it is expressed selectively in serotonergic neurons of the raphe nuclei with a secondary site in the ventral tegmental area (PMID:14960297, PMID:21272616). Genetic ablation establishes that TPH2 is the sole source of brain 5-HT across the lifespan, as Tph2 knockout neurons are entirely devoid of serotonin without compensatory induction of the peripheral paralog TPH1 (PMID:19181488). Critically, the serotonergic identity of raphe neurons—their specification markers and rhythmic electrophysiological properties—is acquired and maintained independently of TPH2-derived 5-HT, even though loss of synthesis produces growth retardation, perinatal lethality, and developmental deficits in respiratory and thermoregulatory control (PMID:22912815, PMID:26869713, PMID:26409296). Enzyme function is set genetically: the mouse C1473G polymorphism and the human-equivalent R439H mutation causally lower brain 5-HT synthesis rate and shift serotonin-dependent behaviors such as aggression and emotionality, while rare coding substitutions (Pro206Ser) reduce enzyme thermal stability (PMID:19006079, PMID:17905754, PMID:21537332). Loss of TPH2 activity reverberates through downstream serotonergic signaling, driving adaptive changes in 5-HT1A, 5-HT1B and 5-HT2A receptors and altering limbic GABA systems, with partial deficits buffered by a compensatory reduction in serotonin degradation (PMID:21537332, PMID:23052836, PMID:24863038). TPH2 output is further tuned post-transcriptionally through alternative splicing into TPH2A and TPH2B isoforms of differing catalytic rate and through RNA editing that suppresses activity (PMID:20126463). Its expression is controlled by glucocorticoid rhythms, NRSF/REST-mediated promoter repression, an Ahi1/GR/ERβ transcriptional axis, ovarian steroids, and H3K9 acetylation (PMID:15857682, PMID:22958208, PMID:21299657, PMID:35643536, PMID:29625215).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2004 High

    Establishing that a distinct, brain-restricted tryptophan hydroxylase gene exists answered why central and peripheral serotonin pools are independently controlled.

    Evidence In situ hybridization across rat brain showing raphe-restricted TPH2 versus pineal TPH1

    PMID:14960297

    Open questions at the time
    • Localization does not establish quantitative contribution to brain 5-HT
    • Does not address regulation of the enzyme
  2. 2009 High

    Knockout demonstrated TPH2 is the exclusive and non-redundant source of brain serotonin, settling whether TPH1 could substitute centrally.

    Evidence Tph2 knockout mouse with immunohistochemistry and isoform mRNA analysis across development

    PMID:19181488

    Open questions at the time
    • Does not resolve which downstream phenotypes are 5-HT-dependent versus developmental
    • No mechanistic detail on enzyme regulation
  3. 2005 Medium

    Linking a single Tph2 polymorphism to graded enzyme activity and aggression showed that natural sequence variation tunes serotonin output and behavior.

    Evidence Midbrain TPH enzyme assays across inbred strains with C1473G genotyping and aggression testing

    PMID:16268992

    Open questions at the time
    • Association across strains confounded by genetic background
    • Mechanism by which C1473G alters activity not defined
  4. 2009 High

    Congenic lines proved the C1473G variant causally determines brain TPH2 activity and behavior, removing background confounds from the earlier association.

    Evidence B6-1473C and B6-1473G congenic mice with enzyme assays and behavioral batteries

    PMID:19006079

    Open questions at the time
    • Molecular basis of the activity difference not structurally defined
    • Behavioral specificity to 5-HT not isolated
  5. 2007 Medium

    Biochemical characterization of a rare human variant showed that destabilizing the enzyme is a plausible route to brain 5-HT deficiency.

    Evidence Recombinant wild-type versus Pro206Ser TPH2 thermal stability and solubility assays

    PMID:17905754

    Open questions at the time
    • In vitro only; in vivo serotonin consequence not measured
    • Single study
  6. 2010 High

    Identifying splice isoforms and RNA editing revealed a post-transcriptional layer fine-tuning serotonin synthesis capacity.

    Evidence cDNA sequencing of human amygdala plus kinetic assays of recombinant TPH2A/TPH2B and editing analysis

    PMID:20126463

    Open questions at the time
    • Physiological abundance and regulation of editing in vivo unclear
    • Functional impact on behavior not tested
  7. 2008 Medium

    Mapping 3'-UTR splice variants and stress responsiveness distinguished TPH2 from stress-inducible TPH1 in the raphe.

    Evidence 3'-RACE, qRT-PCR and ISH in rat dorsal raphe under chronic restraint stress

    PMID:18197473

    Open questions at the time
    • Functional consequence of differing 3'-UTRs not established
    • Stress effect on TPH2 protein/activity not measured
  8. 2011 Medium

    Detection of TPH2 in the VTA extended serotonergic synthesis beyond the raphe into the reward pathway.

    Evidence qRT-PCR, western blot, enzyme activity and immunocytochemistry across rat brain regions

    PMID:21272616

    Open questions at the time
    • Functional role of VTA TPH2 not tested
    • Single lab
  9. 2011 Medium

    Establishing glucocorticoid control of daily tph2 rhythms identified the dominant driver of circadian variation in serotonin synthesis capacity.

    Evidence Adrenalectomy and glucocorticoid implant rescue with quantitative ISH in Syrian hamsters

    PMID:21299657

    Open questions at the time
    • Direct transcriptional mechanism (GR binding to Tph2) not shown here
    • mRNA only, not activity
  10. 2011 High

    A knockin of the human depression-associated R439H mutation demonstrated that partial TPH2 loss produces a graded serotonin deficit with selective receptor adaptations.

    Evidence R439H knockin mice with microdialysis, autoradiography, radioligand binding and physiological readouts

    PMID:21537332

    Open questions at the time
    • Does not establish disease causation in humans
    • 5-HT2A enhancement mechanism not resolved
  11. 2012 High

    Clean constitutive knockout dissociated serotonergic neuron differentiation and identity from endogenous 5-HT, while defining growth and receptor consequences of total deficiency.

    Evidence Tph2 knockout mice with IHC, HPLC, electrophysiology and receptor autoradiography

    PMID:22912815

    Open questions at the time
    • Mechanism of receptor upregulation not defined
    • Cause of leanness/growth retardation unresolved
  12. 2015 High

    In vivo and slice recordings confirmed that the rhythmic firing identity of serotonergic neurons is independent of TPH2 and 5-HT.

    Evidence Whole-cell patch-clamp and single-unit recordings in Tph2-/- mice

    PMID:26409296

    Open questions at the time
    • Basis of altered input conductance/cell size not determined
  13. 2012 High

    Showing SSRIs deplete intraneuronal 5-HT only when synthesis is impaired demonstrated that ongoing TPH2 activity is required to sustain serotonin during transporter blockade.

    Evidence Chronic SSRI treatment with 5-HTP rescue and HPLC in R439H knockin mice

    PMID:23336047

    Open questions at the time
    • Relevance to human SSRI response not established
  14. 2012 Medium

    Mapping limbic GABA changes linked 5-HT deficiency to region-specific inhibitory circuit remodeling.

    Evidence Stereology and HPLC GABA measurements in amygdala, hippocampus and prefrontal cortex of Tph2 knockouts

    PMID:23052836

    Open questions at the time
    • Causal pathway from 5-HT loss to GABA changes not defined
    • Behavioral consequence not linked
  15. 2012 Medium

    Identifying NRSF/REST repression of the TPH2 promoter provided a transcriptional brake tied to neuronal differentiation state.

    Evidence Luciferase reporter with NRSF/REST element mutagenesis in a neuronal cell line

    PMID:22958208

    Open questions at the time
    • In vivo relevance in raphe neurons not confirmed
    • Cell-line context
  16. 2012 High

    Congenic C1473G analysis showed reduced synthesis rate can leave steady-state 5-HT intact yet desensitize 5-HT1A autoreceptors and produce reversible anxiety.

    Evidence Microdialysis, [35S]GTPγS binding, autoradiography and SSRI rescue in congenic 1473G mice

    PMID:22491354

    Open questions at the time
    • Mechanism coupling synthesis rate to autoreceptor sensitivity unclear
  17. 2014 High

    Graded-activity mouse lines revealed a homeostatic buffer: reduced serotonin degradation compensates for lowered synthesis, preserving emotional behavior.

    Evidence Multiple Tph2 lines with HPLC metabolism, 5-HT1A autoradiography and behavioral/temperature tests

    PMID:24863038

    Open questions at the time
    • Molecular basis of compensatory degradation reduction not identified
  18. 2016 High

    A knockout rat with 5-HTP rescue established a causal, age-specific role for TPH2-derived serotonin in respiratory and thermoregulatory development.

    Evidence Tph2-/- rats with plethysmography, body temperature, 5-HTP rescue and HPLC/IHC validation

    PMID:26869713

    Open questions at the time
    • Circuit mechanism for developmental ventilatory deficit not defined
  19. 2016 Medium

    Optogenetic control of tph2 neurons in zebrafish causally linked their activity to light/dark preference behavior.

    Evidence Calcium imaging and bidirectional optogenetics of tph2 neurons with preference assay in larval zebrafish

    PMID:26868164

    Open questions at the time
    • Does not separate neuronal activity from 5-HT synthesis per se
    • Mammalian generalizability untested
  20. 2018 Medium

    Identifying prenatal-stress-induced loss of H3K9 acetylation at Tph2, reversible by HDAC inhibition, defined an epigenetic route to depression-relevant TPH2 repression.

    Evidence Prenatal stress rat model with ChIP for H3K9ac, qRT-PCR/western and TSA rescue plus behavioral tests

    PMID:29625215

    Open questions at the time
    • Sex-specificity mechanism unresolved
    • Causal link from H3K9ac to behavior indirect
  21. 2018 Medium

    Defining the Ahi1/GR/ERβ axis connected stress hormone signaling to ERβ-dependent transcriptional activation of TPH2 and serotonin output.

    Evidence Ahi1 knockout mice with luciferase GR-ERβ assays, ERβ agonist rescue and E2 measurement

    PMID:35643536

    Open questions at the time
    • Direct ERβ binding at the Tph2 promoter not shown
    • Single model system
  22. 2019 Medium

    A knockout rat aggression study showed reduced 5-HT1A sensitivity accompanies serotonin deficiency, contrasting with normal receptor coupling reported in mice.

    Evidence Resident-intruder aggression and NLX-112 dose-response in Tph2 knockout rats

    PMID:31078489

    Open questions at the time
    • Species/model discrepancy with mouse data unresolved
    • Receptor density not directly measured
  23. 2020 Low

    Computational modeling predicted that psychiatric-associated TPH2 coding variants destabilize catalytic and oligomerization domains and dimer interactions.

    Evidence Molecular dynamics simulations and structural/conservation prediction algorithms

    PMID:32119710

    Open questions at the time
    • Computational only; no experimental validation in this work
    • Predictions not tied to measured enzyme activity

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (glucocorticoid rhythms, ERβ, REST, RNA editing, histone acetylation) are integrated to set serotonin synthesis rate in specific raphe subpopulations, and which TPH2-dependent phenotypes are causally relevant to human psychiatric disease, remains unresolved.
  • No unified model integrating transcriptional, post-transcriptional and epigenetic control
  • Human disease causation not established by direct genetic evidence in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-112316 Neuronal System 2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TPH2 is the brain-specific isoform of tryptophan hydroxylase, expressed exclusively in raphe nuclei (and not in peripheral tissues), while TPH1 is expressed predominantly in the pineal gland, with no appreciable overlap between the two paralogs in rat brain as determined by in situ hybridization histochemistry. In situ hybridization histochemistry across Sprague-Dawley rat brain; semiquantitative mRNA measurement Biological psychiatry High 14960297
2009 Raphe neurons of Tph2 knockout mice are completely devoid of brain serotonin, with no compensatory activation of Tph1 expression, establishing that brain serotonin synthesis across the lifespan is exclusively maintained by TPH2. Tph2 knockout mouse model; immunohistochemistry and mRNA expression analysis of 5-HT and TPH isoforms during pre- and postnatal development European neuropsychopharmacology High 19181488
2005 The C1473G single-nucleotide polymorphism in the mouse Tph2 gene is associated with differential brain TPH enzymatic activity: mice homozygous for the 1473C allele show higher midbrain TPH activity than mice carrying the 1473G allele, and this correlates with increased intermale aggression. TPH enzyme activity assay in midbrain tissue from 10 inbred mouse strains; genotyping of C1473G polymorphism; behavioral assay (intermale aggression) Genes, brain, and behavior Medium 16268992
2009 The C1473G polymorphism in the mouse Tph2 gene causally determines TPH2 enzymatic activity in the brain and is linked to aggression intensity and forced-swim immobility, as demonstrated using congenic B6-1473C and B6-1473G lines on a C57BL/6 background. Congenic mouse lines (three successive backcrosses onto C57BL/6); TPH2 enzyme activity assay; behavioral tests (forced swim, intermale aggression, open field) Journal of neuroscience research High 19006079
2007 The Pro206Ser substitution in TPH2 (encoded by rare SNP rs17110563) results in reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism. Recombinant protein expression; biochemical assays for thermal stability and solubility of wild-type vs. Pro206Ser TPH2 Human molecular genetics Medium 17905754
2010 TPH2 pre-mRNAs are alternatively spliced into two isoforms (TPH2a and TPH2b) in human brain, and both splice variants undergo RNA editing. The novel TPH2B protein shows higher enzymatic activity than TPH2A, while RNA editing inhibits enzymatic activity of both variants, revealing post-transcriptional fine-tuning of brain serotonin biosynthesis. cDNA sequence analysis of human post-mortem amygdala; kinetic enzyme activity assays with recombinant TPH2A and TPH2B variants expressed in cell lines; RNA editing analysis PloS one High 20126463
2011 Tph2 knockin mice expressing R439H mutation (equivalent to the human depression-associated mutation) show 80% reduction in 5-HT synthesis, reduced basal and stimulated extracellular 5-HT, reduced CSF 5-HIAA, blunted fenfluramine-induced plasma prolactin, blunted 5-HT1A agonist-induced hypothermia, increased frontal cortex 5-HT2A receptor levels, and enhanced 5-HT2A receptor function, while 5-HT1A receptor levels and G-protein coupling are normal. Tph2 R439H knockin mouse model; in vivo microdialysis; receptor autoradiography; radioligand binding; G-protein coupling assay; body temperature measurements Molecular psychiatry High 21537332
2012 Constitutive Tph2 inactivation (Tph2-/-) results in complete brain 5-HT deficiency, growth retardation, and persistent leanness; raphe neurons lacking Tph2 retain normal electrophysiological properties and expression of serotonergic specification markers (except Tph2 and 5-HT), demonstrating that serotonergic neuron differentiation is independent of endogenous 5-HT synthesis. Additionally, 5-HT deficiency induces upregulation of 5-HT1A and 5-HT1B receptors and a reduction of norepinephrine concentrations. Tph2 constitutive knockout mouse; immunohistochemistry; HPLC for monoamine levels; electrophysiology; receptor autoradiography; gene expression analysis PloS one High 22912815
2012 Chronic SSRI treatment (fluoxetine and paroxetine) dramatically further depletes 5-HT tissue levels in R439H Tph2 knockin mice (to 1–3% of wild-type), while having little effect in wild-type controls; co-treatment with the 5-HT precursor 5-HTP restores 5-HT tissue content and prevents SSRI-induced depletion, demonstrating that ongoing TPH2-dependent synthesis is essential to support intraneuronal 5-HT during SERT blockade. R439H Tph2 knockin mice; chronic SSRI treatment; HPLC measurement of 5-HT tissue content; 5-HTP rescue experiment ACS chemical neuroscience High 23336047
2012 Brain 5-HT deficiency in Tph2 knockout mice differentially alters GABA systems in limbic regions: amygdala shows decreased GABAergic interneuron numbers (particularly parvalbumin-immunoreactive interneurons), hippocampus shows increased GABA concentrations in Tph2-/- mice, while prefrontal cortex shows decreased GABA concentrations selectively in Tph2+/- mice. Tph2 knockout mice; unbiased stereological estimation of interneuron numbers; immunohistochemistry; HPLC-based GABA concentration measurements in limbic brain regions Histochemistry and cell biology Medium 23052836
2005 Ovarian steroids (estrogen alone, or estrogen + progesterone) significantly increase TPH2 mRNA expression in serotonin neurons of macaque midbrain raphe, indicating hormonal regulation of brain serotonin synthesis rate. Spayed macaques treated with hormone implants; in situ hybridization; quantitative RT-PCR of TPH2 mRNA Brain research. Molecular brain research Medium 15857682
2008 In the rat dorsal raphe nucleus, two TPH2 mRNA splice variants (TPH2a with long 3'-UTR and TPH2b with short 3'-UTR) exist; TPH2b is the predominant variant while TPH2a is low abundance. Restraint stress upregulates TPH1 but not TPH2 mRNA in the dorsal raphe nucleus. 3'-RACE; quantitative real-time PCR; in situ hybridization; chronic restraint stress paradigm in male Wistar rats Cellular and molecular neurobiology Medium 18197473
2011 TPH2 mRNA expression and protein are detected in the ventral tegmental area (VTA) of rat brain, with the second-highest TPH2 activity after the raphe, and TPH2-immunopositive cell bodies were identified within the VTA, suggesting serotonergic signaling in the mesolimbic/mesocortical reward pathway. TPH2 mRNA quantification by qRT-PCR; western blot; enzyme activity assay; immunocytochemistry across rat brain regions Brain research bulletin Medium 21272616
2012 TPH2 expression in a neuronal cell line (A1 mes-c-myc) is modulated by neuronal differentiation, and the NRSF/REST transcription factor represses TPH2 promoter activity; mutation of the NRSF/REST responsive element in the TPH2 promoter strongly increases promoter activity upon differentiation. Neuronal cell line differentiation; luciferase reporter assay driven by human TPH2 promoter; NRSF/REST responsive element mutagenesis; RT-PCR and western blot Journal of neurochemistry Medium 22958208
2012 A functional C1473G Tph2 SNP in congenic C57BL/6N mice reduces in vivo brain 5-HT synthesis rate without reducing brain 5-HT concentrations or altering baseline 5-HT release (measured by microdialysis), but causes functional desensitization of 5-HT1A autoreceptors (measured by [35S]GTPγS binding and autoradiography) and produces an anxiety phenotype reversible by chronic escitalopram treatment. Congenic Tph2 1473G C57BL/6N mice; in vivo microdialysis; [35S]GTPγS binding assay; 5-HT1A receptor autoradiography; behavioral anxiety tests; chronic SSRI treatment Neuropsychopharmacology High 22491354
2014 Progressive reduction of TPH2 activity (via Tph2G/G and compound Tph2C/- heterozygous mice) has no effect on emotional behavior despite lowered synthesis rate, because serotonin degradation rate is drastically decreased to compensate; 5-HT1A autoreceptor density and G-protein coupling are unchanged, but hypothermic response to 5-HT1A agonist is attenuated. Multiple Tph2 mouse lines with graded activity reduction; HPLC for serotonin metabolism; quantitative autoradiography for 5-HT1A receptor; behavioral tests; body temperature measurement after 8-OH-DPAT Neuropharmacology High 24863038
2016 Constitutive CNS 5-HT depletion via Tph2 gene knockout in rats (DA Tph2-/- rats lacking TPH immunoreactivity and brain 5-HT) attenuates ventilation and body temperature at specific postnatal ages but not in adults; treatment with 5-HTP partially restores CNS 5-HT and increases ventilation, establishing a causal role for TPH2-dependent serotonin in developmental respiratory and thermoregulatory control. Tph2 knockout rat (dark agouti); whole-body plethysmography; body temperature measurement; 5-HTP rescue; immunohistochemistry for TPH and HPLC for brain 5-HT Journal of applied physiology High 26869713
2015 5-HT neurons in Tph2-/- mice lacking brain 5-HT retain normal firing rates, firing variability, action potential shape, and resting membrane potential in vitro and in vivo, demonstrating that acquisition and maintenance of the characteristic rhythmic electrophysiological properties of serotonergic neurons is independent of TPH2 and endogenous 5-HT. A ~25% higher input conductance was observed in Tph2-/- neurons, associated with slightly larger cell size. Tph2-/- mice; whole-cell patch-clamp in brainstem slice preparation; single-unit recording in anesthetized animals European neuropsychopharmacology High 26409296
2011 Glucocorticoid rhythms are the main regulator of daily tph2 mRNA expression in raphe nuclei: adrenalectomy abolishes nycthemeral variation in tph2 expression, and experimental restoration of a daily glucocorticoid rhythm restores tph2 daily variation in Syrian hamsters. Adrenalectomy and glucocorticoid implant experiments in Syrian hamsters; quantitative in situ hybridization for tph2 mRNA at different time points The European journal of neuroscience Medium 21299657
2018 Ahi1 knockout in mice leads to decreased brain serotonin through inhibition of the ERβ/TPH2 pathway; glucocorticoid receptor (GR) binds to glucocorticoid response elements in the ERβ promoter and represses ERβ transcription, and Ahi1 regulates GR nuclear translocation upon stress. ERβ agonist treatment increases TPH2 expression and 5-HT production, and brain (but not serum) E2 levels are decreased in male Ahi1 KO mice. Ahi1 knockout mice; western blot; dual-luciferase reporter assay; immunofluorescence; gene knockdown; rescue assay with ERβ agonist; ELISA for E2 levels Cell communication and signaling Medium 35643536
2018 Prenatal stress reduces Tph2 mRNA and protein expression in the dorsal raphe nucleus and hippocampus of male juvenile offspring rats and decreases hippocampal Tph2 H3K9 acetylation (H3K9ac); microinjection of the HDAC inhibitor trichostatin A (TSA) reverses these effects, linking reduced H3K9ac to epigenetic repression of Tph2 and depression-like behavior in a sex-specific manner. Prenatal stress rat model; qRT-PCR and western blot for TPH2; chromatin immunoprecipitation-based assessment of H3K9ac at Tph2 locus; TSA microinjection rescue; sucrose preference test; forced swim test Neuroscience Medium 29625215
2019 Tph2 knockout rats with profoundly diminished extracellular serotonin display increased aggressiveness; the anti-aggressive dose-effect curve of the selective 5-HT1A full agonist NLX-112 is shifted to the right in Tph2 KO rats compared to wild-type controls, indicating decreased 5-HT1A receptor sensitivity in Tph2 KO rats (in contrast to reports of normal 5-HT1A receptor levels and G-protein coupling in Tph2 KO mice). Tph2 knockout rats; resident-intruder aggression test; pharmacological dose-response experiment with selective 5-HT1A agonist NLX-112 Neuropharmacology Medium 31078489
2015 Conditional Tph2 knockout mice were generated by Cre-mediated excision of exon 3, resulting in near-complete loss of brain serotonin and recapitulating growth defects and perinatal lethality seen in conventional knockouts. In Tph2null mice (but not wild-types), two distinct Tph2 mRNA isoforms (Tph2Δ3 and Tph2Δ3Δ4) are produced; Tph2Δ3Δ4 carries an in-frame deletion (amino acids 84–178) and may retain residual enzymatic activity, potentially explaining sub-threshold residual brain 5-HT in Tph2null/null mice. Conditional knockout mouse generation (Cre-lox); tamoxifen-inducible inactivation; brain 5-HT quantification by HPLC; RT-PCR for Tph2 mRNA isoforms; immunohistochemistry PloS one Medium 26291320
2020 In silico analysis predicts that TPH2 variants P206S, R303W, and R441H (associated with psychiatric disorders) affect protein flexibility and essential mobility at the catalytic and oligomerization domains, and alter dimer binding affinity and stability; molecular dynamics simulations indicate these mutations impair TPH2 functional interactions. Molecular dynamics simulations (GROMACS); multiple functional prediction algorithms; evolutionary conservation analysis (ConSurf); structural dimer binding affinity analysis PloS one Low 32119710
2016 Activation of tph2-expressing rostral dorsal raphe serotonergic neurons (measured by calcium imaging) occurs when larval zebrafish are in darkness, and these neurons are inhibited in the light; optogenetic activation (channelrhodopsin) or inhibition (halorhodopsin) of tph2 neurons modifies light/dark preference, establishing a causal role for tph2 neuron activity in this behavior. Calcium imaging of tph2-expressing cells in larval zebrafish; optogenetic manipulation (channelrhodopsin and halorhodopsin expression in tph2 neurons); behavioral preference assay Scientific reports Medium 26868164

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Molecular psychiatry 250 15124006
2004 Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland. Biological psychiatry 168 14960297
2004 Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biological psychiatry 160 15476687
2009 Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 127 19181488
2011 Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. Psychoneuroendocrinology 107 21257271
2006 Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Molecular psychiatry 104 17453063
2005 Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Molecular psychiatry 103 15940290
2011 Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Molecular psychiatry 102 21537332
2007 Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder. Human molecular genetics 96 17905754
2006 Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Archives of general psychiatry 84 17015812
2012 TPH2 gene polymorphisms and major depression--a meta-analysis. PloS one 83 22693556
2012 Impacts of brain serotonin deficiency following Tph2 inactivation on development and raphe neuron serotonergic specification. PloS one 83 22912815
2005 Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains. Genes, brain, and behavior 79 16268992
2005 A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques. Brain research. Molecular brain research 77 15857682
2015 Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology 76 25716307
2009 Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus. Neuroscience 72 19647049
2005 Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 70 15768392
2008 Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Molecular psychiatry 69 18427560
2011 Chronic non-invasive corticosterone administration abolishes the diurnal pattern of tph2 expression. Psychoneuroendocrinology 67 21924839
2010 Alternative splicing and extensive RNA editing of human TPH2 transcripts. PloS one 64 20126463
2009 TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression. Progress in neuro-psychopharmacology & biological psychiatry 64 19162119
2018 TPH2 polymorphisms across the spectrum of psychiatric morbidity: A systematic review and meta-analysis. Neuroscience and biobehavioral reviews 54 29775696
2006 Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. The international journal of neuropsychopharmacology 53 17176491
2009 C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase-2 activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test. Journal of neuroscience research 50 19006079
2018 Association between single nucleotide polymorphisms of TPH1 and TPH2 genes, and depressive disorders. Journal of cellular and molecular medicine 49 29314569
2006 Effect of SNP at position 40237 in exon 7 of the TPH2 gene on susceptibility to suicide. Brain research 49 17011525
2020 Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders. Journal of neurology, neurosurgery, and psychiatry 46 32576619
2008 Stress upregulates TPH1 but not TPH2 mRNA in the rat dorsal raphe nucleus: identification of two TPH2 mRNA splice variants. Cellular and molecular neurobiology 46 18197473
2007 Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1. BMC medical genetics 46 17346350
2007 Role of TPH-2 in brain function: news from behavioral and pharmacologic studies. Journal of neuroscience research 45 17492791
2012 Genetic variants in the tryptophan hydroxylase 2 gene (TPH2) and depression during and after pregnancy. Journal of psychiatric research 43 22721547
2013 Regulatory variant of the TPH2 gene and early life stress are associated with heightened attention to social signals of fear in infants. Journal of child psychology and psychiatry, and allied disciplines 42 24304270
2008 TPH2 and TPH1: association of variants and interactions with heroin addiction. Behavior genetics 41 18181017
2005 Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality. Psychiatry research 41 15840421
2012 Elevated tph2 mRNA expression in a rat model of chronic anxiety. Depression and anxiety 40 22511363
2016 Local gyrification index in patients with major depressive disorder and its association with tryptophan hydroxylase-2 (TPH2) polymorphism. Human brain mapping 39 27807918
2012 Association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms. Journal of affective disorders 38 22483952
2012 Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS chemical neuroscience 38 23336047
2016 Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats. Journal of applied physiology (Bethesda, Md. : 1985) 36 26869713
2008 The influence of family structure, the TPH2 G-703T and the 5-HTTLPR serotonergic genes upon affective problems in children aged 10-14 years. Journal of child psychology and psychiatry, and allied disciplines 36 19175813
2012 GABA concentration and GABAergic neuron populations in limbic areas are differentially altered by brain serotonin deficiency in Tph2 knockout mice. Histochemistry and cell biology 35 23052836
2010 Bacopa monniera leaf extract up-regulates tryptophan hydroxylase (TPH2) and serotonin transporter (SERT) expression: implications in memory formation. Journal of ethnopharmacology 35 21129470
2007 No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover. Journal of affective disorders 35 17604842
2020 Maternal high-fat diet stimulates proinflammatory pathway and increases the expression of Tryptophan Hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF) in adolescent mice hippocampus. Neurochemistry international 34 32652271
2011 Influence of TPH2 variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia. Psychiatry research 34 21396719
2008 Molecular cloning, characterization and expression of two tryptophan hydroxylase (TPH-1 and TPH-2) genes in the hypothalamus of Atlantic croaker: down-regulation after chronic exposure to hypoxia. Neuroscience 33 19015006
2017 Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety. Journal of affective disorders 32 28342337
2014 Association of TPH-1 and TPH-2 gene polymorphisms with suicidal behavior: a systematic review and meta-analysis. BMC psychiatry 32 25005534
2016 Activation and inhibition of tph2 serotonergic neurons operate in tandem to influence larval zebrafish preference for light over darkness. Scientific reports 31 26868164
2018 Serotonergic neurotransmission manipulation for the understanding of brain development and function: Learning from Tph2 genetic models. Biochimie 30 30513372
2009 Population-specific functional variant of the TPH2 gene 2755C>A polymorphism contributes risk association to major depression and anxiety in Chinese peripartum women. Archives of women's mental health 30 19588223
2022 Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway involving sexual differences in depressive behaviors. Cell communication and signaling : CCS 28 35643536
2006 Family-based association study of TPH1 and TPH2 polymorphisms in autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 28 16958027
2014 Adaptive changes in serotonin metabolism preserve normal behavior in mice with reduced TPH2 activity. Neuropharmacology 27 24863038
2012 Modifying the role of serotonergic 5-HTTLPR and TPH2 variants on disulfiram treatment of cocaine addiction: a preliminary study. Genes, brain, and behavior 27 22925276
2012 Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: modulation by cell differentiation and NRSF/rest activity. Journal of neurochemistry 26 22958208
2006 The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses. Genes, brain, and behavior 26 16436194
2018 Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus. Neurobiology of stress 25 29520369
2018 TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner. Frontiers in molecular neuroscience 25 30425618
2013 Development × environment interactions control tph2 mRNA expression. Neuroscience 25 23403177
2010 TPH2 polymorphisms and alcohol-related suicide. Neuroscience letters 25 21182896
2008 TPH2 gene variation and conflict processing in a cognitive and an emotional Stroop task. Behavioural brain research 25 19071164
2011 TPH2 in the ventral tegmental area of the male rat brain. Brain research bulletin 24 21272616
2009 The effect of rearing experience and TPH2 genotype on HPA axis function and aggression in rhesus monkeys: a retrospective analysis. Hormones and behavior 24 19900455
2009 TPH2 is not a susceptibility gene for suicide in Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 23 19748542
2020 Stress-induced aggression in heterozygous TPH2 mutant mice is associated with alterations in serotonin turnover and expression of 5-HT6 and AMPA subunit 2A receptors. Journal of affective disorders 22 32553388
2015 Generation of a Tph2 Conditional Knockout Mouse Line for Time- and Tissue-Specific Depletion of Brain Serotonin. PloS one 22 26291320
2011 Polymorphism of the tryptophan hydroxylase 2 (TPH2) gene is associated with chimpanzee neuroticism. PloS one 22 21765945
2010 Linkage of schizophrenia with TPH2 and 5-HTR2A gene polymorphisms in the Malay population. Genetics and molecular research : GMR 22 20623453
2018 TPH-2 Gene Polymorphism in Major Depressive Disorder Patients With Early-Wakening Symptom. Frontiers in neuroscience 21 30519155
2017 Serotonin and the Brain's Rich Club-Association Between Molecular Genetic Variation on the TPH2 Gene and the Structural Connectome. Cerebral cortex (New York, N.Y. : 1991) 21 26975194
2013 Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population. Progress in neuro-psychopharmacology & biological psychiatry 21 23628433
2020 Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior - a TPH2 imaging genetics approach. Psychological medicine 20 32981537
2019 Enhanced aggressive phenotype of Tph2 knockout rats is associated with diminished 5-HT1A receptor sensitivity. Neuropharmacology 20 31078489
2018 H3K9 Acetylation of Tph2 Involved in Depression-like Behavior in Male, but not Female, Juvenile Offspring Rat Induced by Prenatal Stress. Neuroscience 20 29625215
2015 Association analysis of TPH-1 and TPH-2 genes with suicidal behavior in patients with attempted suicide in Mexican population. Comprehensive psychiatry 20 26028568
2014 The effects of Acorus tatarinowii Schott on 5-HT concentrations, TPH2 and 5-HT1B expression in the dorsal raphe of exercised rats. Journal of ethnopharmacology 20 25456438
2007 The role of the TPH1 and TPH2 genes for nicotine dependence: a genetic association study in two different age cohorts. Neuropsychobiology 20 17986837
2004 Identification of genetic variants in the neuronal form of tryptophan hydroxylase (TPH2). Psychiatric genetics 20 15167691
2014 Tryptophan hydroxylase 2 (TPH2) gene polymorphisms and psychiatric comorbidities in temporal lobe epilepsy. Epilepsy & behavior : E&B 19 24491795
2010 TPH2 5'- and 3'-regulatory polymorphisms are differentially associated with HPA axis function and self-injurious behavior in rhesus monkeys. Genes, brain, and behavior 19 20059554
2006 No association between TPH2 gene polymorphisms and ADHD in a UK sample. Neuroscience letters 19 17123708
2017 Effect of childhood general traumas on suicide attempt depends on TPH2 and ADARB1 variants in psychiatric patients. Journal of neural transmission (Vienna, Austria : 1996) 18 28084537
2012 A functional Tph2 C1473G polymorphism causes an anxiety phenotype via compensatory changes in the serotonergic system. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 18 22491354
2021 Meta-analysis of association between TPH2 single nucleotide poiymorphism and depression. Neuroscience and biobehavioral reviews 17 34979191
2020 In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders. PloS one 17 32119710
2020 Altered behaviour, dopamine and norepinephrine regulation in stressed mice heterozygous in TPH2 gene. Progress in neuro-psychopharmacology & biological psychiatry 17 33127424
2020 The relationship between occupational stress, musculoskeletal disorders and the mental health of coal miners: The interaction between BDNF gene, TPH2 gene polymorphism and the environment. Journal of psychiatric research 17 33450468
2014 Association of COMT and TPH-2 genes with DSM-5 based PTSD symptoms. Journal of affective disorders 17 25451452
2012 A detailed association analysis between the tryptophan hydroxylase 2 (TPH2) gene and autism spectrum disorders in a Japanese population. Psychiatry research 17 22361444
2015 Cellular resilience: 5-HT neurons in Tph2(-/-) mice retain normal firing behavior despite the lack of brain 5-HT. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 16 26409296
2025 Electroacupuncture and Tongbian decoction ameliorate CUMS-induced depression and constipation in mice via TPH2/5-HT pathway of the gut-brain axis. Brain research bulletin 15 39814323
2013 Associations Between Variations in TPH1 , TPH2 and SLC6A4 Genes and Postpartum Depression: A Study in the Jordanian Population. Balkan journal of medical genetics : BJMG 15 24265583
2011 Glucocorticoid-mediated nycthemeral and photoperiodic regulation of tph2 expression. The European journal of neuroscience 15 21299657
2010 Common genetic variations in TPH1/TPH2 genes are not associated with schizophrenia in Japanese population. Neuroscience letters 15 20144688
2011 Functional promoter polymorphism of the neuronal isoform of tryptophan hydroxylase (Tph2) in suicide. Psychiatry research 14 20869124
2010 Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting. Genes, brain, and behavior 14 20946355
2017 Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine. Progress in neuro-psychopharmacology & biological psychiatry 13 28456685
2010 Effects of chronic fluoxetine treatment on catalepsy and the immune response in mice with a genetic predisposition to freezing reactions: the roles of types 1A and 2A serotonin receptors and the tph2 and SERT genes. Neuroscience and behavioral physiology 13 20464512
2006 Analysis of variations in the tryptophan hydroxylase-2 (TPH2) gene in cocaine dependence. Addiction biology 13 16759340

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