Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study.

Dysregulation of brain serotonin transmission is an important contributing factor in many psychiatric disorders. Tryptophan hydroxylase (TPH), the rate limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice which was exclusively expressed in the brain. Due to the lack of data about its anatomic expression in humans we performed a mRNA expression analysis comparing TPH1 and TPH2 mRNA in several regions of the human brain (cortex, thalamus, hypothalamus, hippocampus, amygdala, cerebellum and raphe nuclei). The study was performed with post-mortem specimens obtained from eight individuals with sudden deaths, not directly involving CNS diseases. Our results demonstrate that the mRNA of both genes is expressed in each investigated brain region with variations between the brain areas, as well as between the particular genes. The major finding of this study was the high expression level of TPH2 mRNA in the raphe nuclei ( approximately 4-fold more abundant than that of TPH1). The raphe nuclei showed the highest TPH2 mRNA levels at all, compared to the other regions (7-fold higher levels on average). To our knowledge, this is the fist study which demonstrates the localization of TPH1 and TPH2 mRNA in different regions of the human brain. Our findings provide further support for a duality of the serotonergic system and may open up new research strategies for the analysis of the repeatedly observed disturbances in the serotonergic system in patients suffering from several psychiatric disorders.

[1]  G. Tosini,et al.  Diurnal rhythms of tryptophan hydroxylase 1 and 2 mRNA expression in the rat retina , 2004, Neuroreport.

[2]  M. Clark,et al.  Measurement of tryptophan hydroxylase mRNA levels by competitive RT-PCR. , 1998, Brain research. Brain research protocols.

[3]  D. Sugden.  Comparison of circadian expression of tryptophan hydroxylase isoform mRNAs in the rat pineal gland using real‐time PCR , 2003, Journal of neurochemistry.

[4]  K. Doya,et al.  Cerebellar aminergic neuromodulation: towards a functional understanding , 2004, Brain Research Reviews.

[5]  C. Soulage,et al.  Behavioral and neurochemical effects induced by subchronic exposure to 40 ppm toluene in rats , 2003, Pharmacology Biochemistry and Behavior.

[6]  Michael Bader,et al.  Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform , 2003, Science.

[7]  C. Cusin,et al.  Tryptophan hydroxylase gene and major psychoses , 2001, Psychiatry Research.

[8]  I. Khan,et al.  Aroclor 1254 inhibits tryptophan hydroxylase activity in rat brain , 2004, Archives of Toxicology.

[9]  K. Ressler,et al.  Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders , 2000, Depression and anxiety.

[10]  M. Aldegunde,et al.  Differential effects of pinealectomy on amygdala and hippocampus serotonin metabolism , 1991, Journal of pineal research.

[11]  G. Turecki,et al.  Meta-analysis of the association between tryptophan hydroxylase and suicidal behavior. , 2002, American journal of medical genetics.

[12]  B. Bondy,et al.  Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains , 2004, European Neuropsychopharmacology.

[13]  M. Bader,et al.  A unique central tryptophan hydroxylase isoform. , 2003, Biochemical pharmacology.

[14]  F. Artaud,et al.  Regulatory properties of neuronal tryptophan hydroxylase. , 1981, Advances in experimental medicine and biology.

[15]  H. Möller,et al.  SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression , 2004, Molecular Psychiatry.

[16]  Gerald L. Brown,et al.  A tryptophan hydroxylase gene marker for suicidality and alcoholism. , 1998, Archives of general psychiatry.

[17]  P. Brambilla,et al.  GABAergic dysfunction in mood disorders , 2003, Molecular Psychiatry.

[18]  E. Sabban,et al.  Tryptophan hydroxylase mRNA levels are elevated by repeated immobilization stress in rat raphe nuclei but not in pineal gland , 1999, Neuroscience Letters.

[19]  P. Pévet,et al.  Circadian change in tryptophan hydroxylase protein levels within the rat intergeniculate leaflets and raphe nuclei , 2004, Neuroscience.

[20]  E. Sabban,et al.  Role of the 5′ untranslated region (UTR) in the tissue‐specific regulation of rat tryptophan hydroxylase gene expression by stress , 2002, Journal of neurochemistry.

[21]  N. K. Popova,et al.  Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A , 2001, Journal of neuroscience research.

[22]  N. Cairns,et al.  An optimistic view for quantifying mRNA in post-mortem human brain. , 2003, Brain research. Molecular brain research.

[23]  M. Darmon,et al.  Differential control of tryptophan hydroxylase expression in raphe and in pineal gland: Evidence for a role of translation efficiency , 1989, Journal of neuroscience research.

[24]  M. Clark,et al.  Tissue-specific glucocorticoid regulation of tryptophan hydroxylase mRNA levels. , 1997, Brain research. Molecular brain research.

[25]  P. Patel,et al.  Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland , 2004, Biological Psychiatry.

[26]  T. Sotnikova,et al.  Tryptophan Hydroxylase-2 Controls Brain Serotonin Synthesis , 2004, Science.

[27]  H. Möller,et al.  Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase Isoform (TPH2) gene in suicide victims , 2004, Biological Psychiatry.

[28]  V. Arango,et al.  Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei , 2004, Biological Psychiatry.

[29]  E. Shink,et al.  Support for the involvement of TPH2 gene in affective disorders , 2004, Molecular Psychiatry.

[30]  J. Hornung,et al.  The human raphe nuclei and the serotonergic system , 2003, Journal of Chemical Neuroanatomy.

[31]  Scheibel Ab.  The thalamus and neuropsychiatric illness. , 1997 .

[32]  M. Kamali,et al.  Understanding the neurobiology of suicidal behavior , 2001, Depression and anxiety.

[33]  K. Fuxe,et al.  EVIDENCE FOR THE EXISTENCE OF MONOAMINE-CONTAINING NEURONS IN THE CENTRAL NERVOUS SYSTEM. I. DEMONSTRATION OF MONOAMINES IN THE CELL BODIES OF BRAIN STEM NEURONS. , 1964, Acta physiologica Scandinavica. Supplementum.

[34]  N. Cairns,et al.  Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. , 2003, Brain research. Molecular brain research.

[35]  T. Amstislavskaya,et al.  Hypothalamic tryptophan hydroxylase and the hypothalamic-pituitary-adrenocortical response to water deprivation and hydration in vasopressin-deficient and normal rats , 2002, Pflügers Archiv.

[36]  I. Lucki,et al.  The spectrum of behaviors influenced by serotonin , 1998, Biological Psychiatry.