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Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice

  • Basic Neurosciences, Genetics and Immunology - Rapid Communication
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Abstract

The relative contribution of the two tryptophan hydroxylase (TPH) isoforms, TPH1 and TPH2, to brain serotonergic system function is controversial. To investigate the respective role of TPH2 in neuron serotonin (5-HT) synthesis and the role of 5-HT in brain development, mice with a targeted disruption of Tph2 were generated. The preliminary results indicate that in Tph2 knockout mice raphe neurons are completely devoid of 5-HT, whereas no obvious alteration in morphology and fiber distribution are observed. The findings confirm the exclusive specificity of Tph2 in brain 5-HT synthesis and suggest that Tph2-synthesized 5-HT is not required for serotonergic neuron formation.

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References

  • Baehne CG, Ehlis AC, Plichta MM, Conzelmann A, Pauli P, Jacob C, Gutknecht L, Lesch KP, Fallgatter AJ (2008) Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Mol Psychiatry (Online 22 April 2008)

  • Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 105:1333–1338

    Article  PubMed  CAS  Google Scholar 

  • Briscoe J, Sussel L, Serup P, Hartigan-O’Connor D, Jessell TM, Rubenstein JL, Ericson J (1999) Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398:622–627

    Article  PubMed  CAS  Google Scholar 

  • Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP (2005) Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 112:1479–1485

    Article  PubMed  CAS  Google Scholar 

  • Côté F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G (2003) Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 100:13525–13530

    Article  PubMed  Google Scholar 

  • Di Pino G, Moessner R, Lesch P, Lauder J, Persico A (2004) Roles for serotonin in neurodevelopment: more than just neural transmission. Curr Neuropharmacol 2:403–418

    Article  CAS  Google Scholar 

  • Ding YQ, Marklund U, Yuan W, Yin J, Wegman L, Ericson J, Deneris E, Johnson RL, Chen ZF (2003) Lmx1b is essential for the development of serotonergic neurons. Nat Neurosci 6:933–938

    Article  PubMed  CAS  Google Scholar 

  • Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012

    Article  PubMed  CAS  Google Scholar 

  • Gundlah C, Alves SE, Clark JA, Pai LY, Schaeffer JM, Rohrer SP (2005) Estrogen receptor-beta regulates tryptophan hydroxylase–1 expression in the murine midbrain raphe. Biol Psychiatry 57:938–942

    Article  PubMed  CAS  Google Scholar 

  • Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Muller J, Zeng Y, Markert C, Escher A, Wendland J, Reif A, Mossner R, Gross C, Brocke B, Lesch KP (2007) Tryptophan hydroxylase–2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol 10:309–320

    Article  PubMed  CAS  Google Scholar 

  • Harvey M, Shink E, Tremblay M, Gagne B, Raymond C, Labbe M, Walther DJ, Bader M, Barden N (2004) Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 9:980–981

    Article  PubMed  CAS  Google Scholar 

  • Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron 37:233–247

    Article  PubMed  CAS  Google Scholar 

  • Herrmann MJ, Huter T, Muller F, Muhlberger A, Pauli P, Reif A, Renner T, Canli T, Fallgatter AJ, Lesch KP (2007) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 17:1160–1163

    Article  PubMed  Google Scholar 

  • Malek ZS, Dardente H, Pevet P, Raison S (2005) Tissue-specific expression of tryptophan hydroxylase mRNAs in the rat midbrain: anatomical evidence and daily profiles. Eur J Neurosci 22:895–901

    Article  PubMed  Google Scholar 

  • McKinney J, Knappskog PM, Haavik J (2005) Different properties of the central and peripheral forms of human tryptophan hydroxylase. J Neurochem 92:311–320

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Sugawara Y, Sawabe K, Ohashi A, Tsurui H, Xiu Y, Ohtsuji M, Lin QS, Nishimura H, Hasegawa H, Hirose S (2006) Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels. J Neurosci 26:530–534

    Article  PubMed  CAS  Google Scholar 

  • Patel PD, Pontrello C, Burke S (2004) Robust and tissue-specific expression of TPH2 versus TPH1 in rat raphe and pineal gland. Biol Psychiatry 55:428–433

    Article  PubMed  CAS  Google Scholar 

  • Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schutz G (1999) Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 23:99–103

    Article  PubMed  CAS  Google Scholar 

  • Vitalis T, Cases O, Passemard S, Callebert J, Parnavelas JG (2007) Embryonic depletion of serotonin affects cortical development. Eur J Neurosci 26:331–344

    Article  PubMed  Google Scholar 

  • Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knolker U, Friedel S, Schafer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 10:1126–1132

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673–1680

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG (2004) Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305:217

    Article  PubMed  CAS  Google Scholar 

  • Zhao ZQ, Scott M, Chiechio S, Wang JS, Renner KJ, Gereau RWT, Johnson RL, Deneris ES, Chen ZF (2006) Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity. J Neurosci 26:12781–12788

    Article  PubMed  CAS  Google Scholar 

  • Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J, Enoch MA, Virkkunen M, Goldman D (2005) Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 62:1109–1118

    Article  PubMed  CAS  Google Scholar 

  • Zill P, Buttner A, Eisenmenger W, Moller HJ, Ackenheil M, Bondy B (2007) Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study. J Psychiatr Res 41:168–173

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to S. Wiese for providing cloning vectors and construct advise as well as to M. Sendtner, C. Gross and P. Gaspar for helpful discussions and continuing support. The authors also thank N. Steigerwald for the genotyping of mice and H. Brunner for expertise in animal husbandry. This research is supported by the Deutsche Forschungsgemeinschaft (SFB 581; KFO 125; GRK 1253 fellowship to C·K., GSLS fellowship to J.W.), European Commission (NEWMOOD LSHMCT-2003-503474), and the Bundesministerium für Bildung und Forschung (IZKF 01 KS 9603).

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Authors and Affiliations

  1. Molecular and Clinical Psychobiology, Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Wuerzburg, Germany

    Lise Gutknecht, Jonas Waider, Stefanie Kraft, Claudia Kriegebaum, Andreas Reif, Angelika Schmitt & Klaus-Peter Lesch

  2. Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Versbacherstrasse 9, 97078, Wuerzburg, Germany

    Bettina Holtmann

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  1. Lise Gutknecht
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  2. Jonas Waider
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  3. Stefanie Kraft
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  4. Claudia Kriegebaum
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  6. Andreas Reif
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  7. Angelika Schmitt
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  8. Klaus-Peter Lesch
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Correspondence to Lise Gutknecht or Klaus-Peter Lesch.

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Gutknecht, L., Waider, J., Kraft, S. et al. Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice. J Neural Transm 115, 1127–1132 (2008). https://doi.org/10.1007/s00702-008-0096-6

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  • DOI: https://doi.org/10.1007/s00702-008-0096-6

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