Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The developmental role of serotonin: news from mouse molecular genetics

Key Points

  • A limited number of neurons are specified to become serotonergic during development. In the central nervous system, this involves a sequence of transcription factors, such as Nkx2.2, Lmx1 and Pet1, that specify the 5-HT cell lineage within a restricted region of the ventral mesencephalon. Synthesis of serotonin in the periphery involves a different isoform of tryptophan hydoxylase and possibly other specification pathways.

  • A partial serotonergic phenotype is transiently observed during development in the limbic cortex, thalamus, hypothalamus, brainstem and peripheral sensory neurons. These neurons do not synthesize 5-HT but transiently express the high-affinity 5-HT transporter and the vesicular monoamine transporter, allowing them to capture and store 5-HT. Extinction of these transient expressions is controlled, in part, by thyroid hormones.

  • Studies of several knockout mouse strains in which 5-HT metabolism is abnormal, such as monoamine oxidase A, serotonin transporter and vesicular monoamine transporter knockout mice, indicate that a tight control of 5-HT is required during the period of refinement of brain connections. This is exemplified by altered development of the primary somatosensory cortex, the retinal projections and the spinal respiratory centres in these mice. The processes that have been found to be controlled by 5-HT levels in these in vivo models are axonal and dendritic remodelling, neuronal survival and neurogenesis.

  • Knockouts and conditional knockouts for the genes that encode specific 5-HT receptor subtypes indicate that different 5-HT receptors control different developmental processes. For instance, 5-HT1B receptors are involved in axon arbour remodelling, 5-HT2B receptors in cell survival and 5-HT1A receptors in adult neurogenesis. Disturbance of these processes during the perinatal period has important consequences for adult behaviour. Investigations of genetic models with 5-HT target molecules provide interesting perspectives on developmental changes in the physiology of several psychiatric disorders.

Abstract

New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Serotonergic specification.
Figure 2: Uptake of serotonin (5-HT) in mature cells and developing neurons.
Figure 3: Effects of excessive stimulation of the 5-HT1B receptor on the refinement of axonal arbours.

Similar content being viewed by others

References

  1. Lipton, S. A. & Kater, S. B. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci. 12, 265–270 (1989).

    CAS  PubMed  Google Scholar 

  2. Lauder, J. M. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 16, 233–239 (1993).

    CAS  PubMed  Google Scholar 

  3. Levitt, P., Harvey, J. A., Friedman, E., Simansky, K. & Murphy, E. H. New evidence for neurotransmitter influences on brain development. Trends Neurosci. 20, 269–274 (1997).

    CAS  PubMed  Google Scholar 

  4. Azmitia, E. C. Modern view on an ancient chemical: serotonin effects on proliferation, maturation, and apoptosis. Brain Res. Bull. 56, 414–424 (2001).

    Google Scholar 

  5. Vitalis, T. & Parnavelas, J. Serotonin and cortical development. Exp. Neurol. 25, 245–256 (2003).

    CAS  Google Scholar 

  6. Whitaker-Azmitia, P. M. Serotonin and brain development: role in human developmental diseases. Brain Res. Bull. 56, 479–485 (2001).

    CAS  PubMed  Google Scholar 

  7. Gingrich, J. A. & Hen, R. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl.) 155, 1–10 (2001).

    CAS  Google Scholar 

  8. Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002). This paper is an elegant genetic demonstration that the behavioural disorders that are induced by the lack of a 5-HT receptor are due to developmental defects occurring during the first weeks of postnatal life.

    CAS  PubMed  Google Scholar 

  9. Dahlstrom, A. & Fuxe, K. Localization of monoamines in the lower brain stem. Experientia 20, 398–399 (1964).

    CAS  PubMed  Google Scholar 

  10. Lidov, H. G. & Molliver, M. E. An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res. Bull. 8, 389–430 (1982).

    CAS  PubMed  Google Scholar 

  11. Wallace, J. A. & Lauder, J. M. Development of the serotonergic system in rat embryo: an immunocytochemical study. Brain Res. Bull. 10, 459–479 (1983).

    CAS  PubMed  Google Scholar 

  12. Jacobs, B. L. & Azmitia, E. C. Structure and function of the brain serotonin system. Physiol. Rev. 72, 165–220 (1992).

    CAS  PubMed  Google Scholar 

  13. Levitt, P. & Rakic, P. The time of genesis, embryonic origin and differentiation of the brain stem monoamine neurons in the rhesus monkey. Brain Res. 256, 35–57 (1982).

    CAS  PubMed  Google Scholar 

  14. Goridis, C. & Rohrer, H. Specification of catecholaminergic and serotoninergic neurons. Nature Rev. Neurosci. 3, 531–541 (2002).

    CAS  Google Scholar 

  15. Ye, W., Shimamura, K., Rubenstein, G., Hynes, M. A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998). This is a seminal paper that analyses how different morphogenetic factors concur to specify whether neurons in the mesencephalon become dopaminergic or serotonergic.

    CAS  PubMed  Google Scholar 

  16. Brodski, C. et al. Location and size of dopaminergic and serotoninergic cell populations are controlled by the position of the midbrain–hindbrain organizer. J. Neurosci. 23, 4199–4207 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hynes, M. et al. The seven-transmembrane receptor smoothened cell-autonomously induces multiple ventral cell types. Nature Neurosci. 3, 41–46 (2000).

    CAS  PubMed  Google Scholar 

  18. Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded sonic hedgehog signalling. Nature 398, 622–627 (1999).

    CAS  PubMed  Google Scholar 

  19. Van Doorninck, J. H. et al. GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei. J. Neurosci. 19, RC12 1–8 (1999).

    CAS  PubMed  Google Scholar 

  20. Hendricks, T. J., Francis, N., Fyodorov, D. J. & Deneris, E. S. The ETS domain factor Pet-1 is an early and precise marker of central 5-HT neurons and interacts with a conserved element in serotonergic genes. J. Neurosci. 19, 10348–10356 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pfaar, H. et al. mPet-1, a mouse ETS-domain transcription factor, is expressed in central serotonergic neurons. Dev. Genes Evol. 212, 43–46 (2002).

    CAS  PubMed  Google Scholar 

  22. Hendricks, T. J. et al. pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behaviour. Neuron 37, 233–247 (2003). These researchers discovered a transcription factor that is selectively expressed in the raphe neurons. As shown in knockout mice, the gene ( Pet1 ) is required for the terminal differentiation of most of the raphe neurons.

    CAS  PubMed  Google Scholar 

  23. De Vitry, F., Hamon, M., Catelon, J., Dubois, M. & Thibault, J. Serotonin initiates and autoamplifies its own synthesis during mouse central nervous system development. Proc. Natl Acad. Sci. USA 83, 8629–8633 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Galter, D. & Unsicker, K. Sequential activation of the 5-HT1A serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Am. J. Anat. 15, 446–455 (2000).

    CAS  Google Scholar 

  25. Whitaker-Azmitia, P. M. & Azmitia, E. C. Stimulation of astroglial serotonin receptors produces culture media which regulates growth of serotonergic neurons. Brain Res. 497, 80–85 (1989).

    CAS  PubMed  Google Scholar 

  26. Branchereau, P., Chapron, J. & Meyrand, P. Descending 5-hydroxytryptamine raphe inputs repress the expression of serotonergic neurons and slow the maturation of inhibitory systems in mouse embryonic spinal cord. J. Neurosci. 22, 2598–2606 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Cases, O. et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268, 1763–1766 (1995). The authors generated a model in which 5-HT levels are dramatically increased in the brain during development. Furthermore, mice lacking Maoa exhibit aggressive behaviours, comparable to patients with a mutation of MAOA.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Fon, E. A. et al. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19, 1271–1283 (1997). This paper showed that a grossly normal development of the brain and of monoamine structures occurs despite the lack of monoaminergic transmission. However, mice die at birth, preventing the evaluation of late developmental processes.

    CAS  PubMed  Google Scholar 

  29. Dumas, S., Darmon, M. C., Delort, J. & Mallet, J. Differential control of tryptophan hydroxylase expression in raphe and in pineal gland: evidence for a role of translation efficiency. J. Neurosci. Res. 24, 537–547 (1989).

    CAS  PubMed  Google Scholar 

  30. Walther, D. J. et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76 (2003).

    CAS  PubMed  Google Scholar 

  31. Gershon, M. D. Genes and lineages in the formation of the enteric nervous system. Curr. Opin. Neurobiol. 7, 101–109 (1997).

    CAS  PubMed  Google Scholar 

  32. Lauder, J. M., Tamir, H. & Sadler, T. W. Serotonin and morphogenesis. I. Sites of serotonin uptake and binding protein immunoreactivity in the midgestation mouse embryo. Development 102, 709–720 (1988). This paper was one of the first to describe sites of storage of 5-HT in cells that do not produce it, and to suggest the importance of these storage sites for controlling 5-HT levels during development.

    CAS  PubMed  Google Scholar 

  33. Shuey, D. L., Sadler, T. W. & JM, L. Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. Teratology 46, 367–378 (1992).

    CAS  PubMed  Google Scholar 

  34. Wallace, J. A. Monoamines in the early chick embryo: demonstration of serotonin synthesis and the regional distribution of serotonin-concentrating cells during morphogenesis. Am. J. Anat. 165, 261–276 (1982).

    CAS  PubMed  Google Scholar 

  35. Lebrand, C. et al. Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17, 823–835 (1996). This paper demonstrated that what was thought to be a transient serotonergic innervation of the cortex corresponded to thalamic axons that had taken up 5-HT.

    CAS  PubMed  Google Scholar 

  36. Cases, O. et al. Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs. J. Neurosci. 18, 6914–6927 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Upton, A. L. et al. Excess of serotonin (5-HT) alters the segregation of ipsilateral and contralateral retinal projections in monoamine oxidase A knock-out mice: possible role of 5-HT uptake in retinal ganglion cells during development. J. Neurosci. 19, 7007–7024 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lebrand, C. et al. Transient developmental expression of monoamine transporters in the rodent forebrain. J. Comp. Neurol. 401, 506–524 (1998).

    CAS  PubMed  Google Scholar 

  39. Hansson, S. R., Mezey, E. & Hoffman, B. J. Serotonin transporter messenger RNA in the developing rat brain: early expression in serotonergic neurons and transient expression in non-serotonergic neurons. Neuroscience 83, 1185–1201 (1998).

    CAS  PubMed  Google Scholar 

  40. Vitalis, T. et al. Developmental expression of monoamine oxidases A and B in the central and peripheral nervous systems of the mouse. J. Comp. Neurol. 442, 331–347 (2002).

    CAS  PubMed  Google Scholar 

  41. Kristt, D. A. Development of neocortical circuitry: quantitative ultrastructural analysis of putative monoaminergic synapses. Brain Res. 178, 69–88 (1979).

    CAS  PubMed  Google Scholar 

  42. Dori, I. E., Dinopoulos, A. & Parnavelas, J. G. The development of the synaptic organization of the serotonergic system differs in brain areas with different functions. Exp. Neurol. 154, 113–125 (1998).

    CAS  PubMed  Google Scholar 

  43. Launay, G., Costa, J. L., Da Prada, M. & Launay, J. M. Estimation of rate constants for serotonin uptake and compartmentation in normal human platelets. Am. J. Physiol. 266, R1061–R1075 (1994).

    CAS  PubMed  Google Scholar 

  44. Tamir, H. et al. Expression and development of a functional plasmalemmal 5- hydroxytryptamine transporter by thyroid follicular cells. Endocrinology 137, 4475–4486 (1996).

    CAS  PubMed  Google Scholar 

  45. Wade, P. R. et al. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J. Neurosci. 16, 2352–2364 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Richards, K. S., Simon, D. J., Pulver, S. R., Beltz, B. S. & Marder, E. Serotonin in the developing stomatogastric system of the lobster, Homarus americanus. J. Neurobiol. 54, 380–392 (2003).

    CAS  PubMed  Google Scholar 

  47. Verney, C., Lebrand, C. & Gaspar, P. Changing distribution of monoaminergic markers in the developing human cerebral cortex with special emphasis on the serotonin transporter. Anat. Rec. 267, 87–93 (2002).

    PubMed  Google Scholar 

  48. Bruning, G. & Liangos, O. Transient expression of the serotonin transporter in the developing mouse thalamocortical system. Acta Histochem. 99, 117–121 (1997).

    CAS  PubMed  Google Scholar 

  49. Fujimiya, M., Kimura, H. & Maeda, T. Postnatal development of serotonin nerve fibers in the somatosensory cortex of mice studied by immunohistochemistry. J. Comp. Neurol. 246, 191–201 (1986).

    CAS  PubMed  Google Scholar 

  50. D'Amato, R. J. et al. Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas. Proc. Natl Acad. Sci. USA 84, 4322–4326 (1987). This striking description of transient 5-HT innervation patterns in the primary sensory cortex incited a number of research groups, including our own, to work on this subject.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Rhoades, R. W. et al. Development and lesion induced reorganization of the cortical representation of the rat's body surface as revealed by immunocytochemistry for serotonin. J. Comp. Neurol. 293, 190–207 (1990).

    CAS  PubMed  Google Scholar 

  52. Whitworth, T. L, Herndon, L. C & Quick, M. W. Psychostimulants differentially regulate serotonin transporter expression in thalamocortical neurons. J. Neurosci. 22, RC192 1–6 (2001).

    Google Scholar 

  53. Hansson, S. R., Cabrera-Vera, T. M. & Hoffman, B. J. Infraorbital nerve transection alters serotonin transporter expression in sensory pathways in early postnatal rat development. Brain Res. Dev. Brain Res. 111, 305–314 (1998).

    CAS  PubMed  Google Scholar 

  54. Quick, M. W. Role of syntaxin 1A on serotonin transporter expression in developing thalamocortical neurons. Int. J. Dev. Neurosci. 20, 219–224 (2002).

    CAS  PubMed  Google Scholar 

  55. Auso, E. et al. Protracted expression of serotonin transporter and altered thalamocortical projections in the barrelfield of hypothyroid rats. Eur. J. Neurosci. 14, 1968–1980 (2001).

    CAS  PubMed  Google Scholar 

  56. Beltz, B. S., Benton, J. L. & Sullivan, J. M. Transient uptake of serotonin by newborn olfactory projection neurons. Proc. Natl Acad. Sci. USA 98, 12730–12735 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Brezun, J. M. & Daszuta, A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89, 999–1002 (1999).

    CAS  PubMed  Google Scholar 

  58. Brezun, J. M. & Daszuta, A. Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. Eur. J. Neurosci. 12, 391–396 (2000).

    CAS  PubMed  Google Scholar 

  59. Jacobs, B. L. Adult brain neurogenesis and depression. Brain Behav. Immunol. 16, 602–609 (2002).

    CAS  Google Scholar 

  60. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). This paper addresses the issue of the effects of 5-HT on adult neurogenesis by genetic approaches, and demonstrates the crucial role of the 5-HT 1A receptor in this process.

    CAS  PubMed  Google Scholar 

  61. Cases, O. et al. Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16, 297–307 (1996). This study was the first to show that high levels of 5-HT during the first postnatal week in mice cause permanent developmental defects, with alterations in the formation of the primary somatosensory cortex.

    CAS  PubMed  Google Scholar 

  62. Rebsam, A., Seif, I. & Gaspar, P. Refinement of thalamocortical arbors and emergence of barrel domains in the primary somatosensory cortex: role of 5-HT. J. Neurosci. 22, 8541–8552 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Vitalis, T. et al. Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period. J. Comp. Neurol. 393, 169–184 (1998).

    CAS  PubMed  Google Scholar 

  64. Bou-Flores, C. et al. Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess. J. Neurosci. 20, 4646–4656 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Vacher, C. M. et al. Monoaminergic control of vasopressin and VIP expression in the mouse suprachiasmatic nucleus. J. Neurosci. Res. 71, 791–801 (2003).

    CAS  PubMed  Google Scholar 

  66. Salichon, N. et al. Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase and 5-HT transporter knock-out mice. J. Neurosci. 21, 884–896 (2001). This paper offered a powerful genetic demonstration of the developmental effects of the 5-HT 1B receptor on the formation of the barrel field and retinal projections.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Persico, A. M. et al. Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J. Neurosci. 21, 6862–6873 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Persico, A. M. et al. Reduced programmed cell death in brains of serotonin transporter knockout mice. Neuroreport 14, 341–344 (2003).

    CAS  PubMed  Google Scholar 

  69. Wang, Y. M. et al. Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19, 1285–1296 (1997).

    CAS  PubMed  Google Scholar 

  70. Takahashi, N. et al. VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc. Natl Acad. Sci. USA 94, 9938–9943 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Alvarez, C. et al. Effects of genetic depletion of monoamines on somatosensory cortical development. Neuroscience 115, 753–764 (2002).

    CAS  PubMed  Google Scholar 

  72. Cases, O. et al. Serotonin influences the developmental cell death in the supragranular neurons of the frontal cortex. Soc. Neurosci. Abstr. 29.18 (2001).

  73. Lauder, J. M. & Krebs, H. Serotonin as a differentiation signal in early neurogenesis. Dev. Neurosci. 1, 15–30 (1978).

    CAS  PubMed  Google Scholar 

  74. Choi, D. S., Ward, S. J., Messaddeq, N., Launay, J. M. & Maroteaux, L. 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development 124, 1745–1755 (1997).

    CAS  PubMed  Google Scholar 

  75. Durig, J. & Hornung, J. P. Neonatal serotonin depletion affects developing and mature mouse cortical neurons. Neuroreport 11, 833–837 (2000).

    CAS  PubMed  Google Scholar 

  76. Côté, F. et al. Disruption of the non-neuronal TPH1 gene demonstrates the importance of peripheral 5-HT in cardiac function. Proc. Natl Acad. Sci. USA (in the press).

  77. Raymond, J. R. et al. Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol. Ther. 92, 179–212 (2001).

    CAS  PubMed  Google Scholar 

  78. van Hooft, J. A. & Yakel, J. L. 5-HT3 receptors in the CNS: 3B or not 3B? Trends Pharmacol. Sci. 24, 157–160 (2003).

    CAS  PubMed  Google Scholar 

  79. Hillion, J., Catelon, J., Raid, M., Hamon, M. & De Vitry, F. Neuronal localization of 5-HT1A receptor mRNA and protein in rat embryonic brain stem cultures. Brain Res. Dev. Brain Res. 79, 195–202 (1994).

    CAS  PubMed  Google Scholar 

  80. Miquel, M. C. et al. Postnatal development and localization of 5-HT1A receptor mRNA in rat forebrain and cerebellum. Brain Res. Dev. Brain Res. 80, 149–157 (1994).

    CAS  PubMed  Google Scholar 

  81. Talley, E. M., Sadr, N. N. & Bayliss, D. A. Postnatal development of serotonergic innervation, 5-HT1A receptor expression, and 5-HT responses in rat motoneurons. J. Neurosci. 17, 4473–4485 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Gould, E. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21, 46S–51S (1999).

    CAS  PubMed  Google Scholar 

  83. Lavdas, A. A., Blue, M., E Lincoln, J. & Parnavelas, J. G. Serotonin promotes the differentiation of glutamate neurons in organotypic slice cultures of developing cerebral cortex. J. Neurosci. 17, 7872–7880 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Yan, W., Wilson, C. C. & Haring, J. H. 5-HT1A receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. Brain Res. Dev. Brain Res. 98, 185–190 (1997).

    CAS  PubMed  Google Scholar 

  85. Boschert, U., Aït Amara, D., Segu, L. & Hen, R. The mouse 5-hydroxytryptamine 1B receptor is localized predominantly on axon terminals. Neuroscience 58, 167–182 (1994).

    CAS  PubMed  Google Scholar 

  86. Bennett-Clarke, C. A., Leslie, M. J., Chiaia, N. L. & Rhoades, R. W. Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Proc. Natl Acad. Sci. USA 90, 153–157 (1993). The first clear demonstration of transient expression of a 5-HT receptor subtype on a well-defined neuronal population and during a sensitive developmental time window.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Laurent, A. et al. Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice. J. Neurosci. 22, 886–900 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Mooney, R. D., Shi, M. Y. & Rhoades, R. W. Modulation of retinotectal transmission by presynaptic 5-HT1B receptors in the superior colliculus of the adult hamster. J. Neurophysiol. 72, 3–13 (1994).

    CAS  PubMed  Google Scholar 

  89. Lotto, B., Upton, L., Price, D. J. & Gaspar, P. Serotonin receptor activation enhances neurite outgrowth of thalamic neurons in rodents. Neurosci. Lett. 269, 87–90 (1999).

    CAS  PubMed  Google Scholar 

  90. Upton, A. L. et al. Lack of 5-HT1B receptor and of serotonin transporter have a different effect on the segregation of retinal axons in the lateral geniculate nucleus and the superior colliculus. Neuroscience 111, 597–610 (2002).

    CAS  PubMed  Google Scholar 

  91. Chen, C. & Regehr, W. G. Presynaptic modulation of the retinogeniculate synapse. J. Neurosci. 23, 3130–3135 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Volgin, D. V., Fay, R. & Kubin, L. Postnatal development of serotonin 1B, 2A and 2C receptors in brainstem motoneurons. Eur. J. Neurosci. 17, 1179–1188 (2003).

    PubMed  Google Scholar 

  93. Roth, B. L., Hamblin, M. W. & Ciaranello, R. D. Developmental regulation of 5-HT2 and 5-HT1C mRNA and receptor levels. Brain Res. Dev. Brain Res. 58, 51–58 (1991).

    CAS  PubMed  Google Scholar 

  94. Vaidya, V. A., Marek, G. J., Aghajanian, G. K. & Duman, R. S. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785–2795 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Dooley, A. E., Pappas, I. S. & Parnavelas, J. G. Serotonin promotes the survival of cortical glutamatergic neurons in vitro. Exp. Neurol. 148, 205–214 (1997).

    CAS  PubMed  Google Scholar 

  96. Dyck, R. H. & Cynader, M. S. Autoradiographic localization of serotonin receptor subtypes in cat visual cortex: transient regional, laminar, and columnar distributions during postnatal development. J. Neurosci. 13, 4316–4338 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kojic, L. et al. Columnar distribution of serotonin-dependent plasticity within kitten striate cortex. Proc. Natl Acad. Sci. USA 97, 1841–1844 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, Y., Gu, Q. & Cynader, M. S. Blockade of serotonin-2C receptors by mesulergine reduces ocular dominance plasticity in kitten visual cortex. Exp. Brain Res. 114, 321–328 (1997).

    CAS  PubMed  Google Scholar 

  99. Gu, Q. & Singer, W. Involvement of serotonin in developmental plasticity of kitten visual cortex. Eur. J. Neurosci. 7, 1146–1153 (1995).

    CAS  PubMed  Google Scholar 

  100. Edagawa, Y., Saito, H. & Abe, K. Endogenous serotonin contributes to a developmental decrease in long-term potentiation in the rat visual cortex. J. Neurosci. 21, 1532–1537 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Tecott, L. H. et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374, 542–546 (1995).

    CAS  PubMed  Google Scholar 

  102. Nebigil, C. G., Launay, J. M., Hickel, P., Tournois, C. & Maroteaux, L. 5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways. Proc. Natl Acad. Sci. USA 97, 2591–2596 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Fiorica-Howells, E., Maroteaux, L. & Gershon, M. D. Serotonin and the 5-HT2B receptor in the development of enteric neurons. J. Neurosci. 20, 294–305 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Nebigil, C. G., Etienne, N., Messaddeq, N. & Maroteaux, L. Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B-receptor signaling. FASEB J. 17, 1373–1375 (2003).

    CAS  PubMed  Google Scholar 

  105. Nebigil, C. G. et al. Serotonin 2B receptor is required for heart development. Proc. Natl Acad. Sci. USA 97, 9508–9513 (2000). The role of 5-HT 2B receptors in early development received a clear demonstration with this knockout mouse that displayed altered development of the heart.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Jolimay, N., Franck, L., Langlois, X., Hamon, M. & Darmon, M. Dominant role of the cytosolic C-terminal domain of the rat 5-HT1B receptor in axonal-apical targeting. J. Neurosci. 20, 9111–9118 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Cornea-Hebert, V. et al. Similar ultrastructural distribution of the 5-HT2A serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat. Neuroscience 113, 23–35 (2002).

    CAS  PubMed  Google Scholar 

  108. Cornea-Hebert, V., Riad, M., Wu, C., Singh, S. K. & Descarries, L. Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J. Comp. Neurol. 409, 187–209 (1999).

    CAS  PubMed  Google Scholar 

  109. Bonasera, S. J. & Tecott, L. H. Mouse models of serotonin receptor function: towards a genetic dissection of serotonin systems. Pharmacol. Therapeutics 88, 133–142 (2000).

    CAS  Google Scholar 

  110. Saudou, F. et al. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265, 1875–1878 (1994).

    CAS  PubMed  Google Scholar 

  111. Buznikov, G. A, Lambert, H. W. & JM, L. Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis. Cell Tissue Res. 305, 177–186 (2001).

    CAS  PubMed  Google Scholar 

  112. Goldberg, J. L. Serotonin regulation of neurite outgrowth in identified neurons from mature and embryonic Helisoma trivolvis. Perspect. Dev. Neurobiol. 5, 373–387 (1998).

    CAS  PubMed  Google Scholar 

  113. Zhou, F. Q. & Cohan, C. S. Growth cone collapse through coincident loss of actin bundles and leading edge actin without actin depolymerization. J. Cell Biol. 28, 1071–1084 (2001).

    Google Scholar 

  114. Castellucci, V., Pinsker, H., Kupfermann, I. & Kandel, E. R. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1745–1748 (1970).

    CAS  PubMed  Google Scholar 

  115. Brunelli, M., Castellucci, V. & Kandel, E. R. Synaptic facilitation and behavioral sensitization in Aplysia: possible role of serotonin and cyclic AMP. Science 194, 1178–1181 (1976).

    CAS  PubMed  Google Scholar 

  116. Dale, N., Kandel, E. R. & Schacher, S. Serotonin produces long-term changes in the excitability of Aplysia sensory neurons in culture that depend on new protein synthesis. J. Neurosci. 7, 2232–2238 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Glanzman, D. L., Kandel, E. R. & Schacher, S. Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons. Science 249, 799–802 (1990).

    CAS  PubMed  Google Scholar 

  118. Dash, P. K., Hochner, B. & Kandel, E. R. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721 (1990).

    CAS  PubMed  Google Scholar 

  119. Bailey, C. H., Chen, M., Keller, F. & Kandel, E. Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia. Science 256, 645–649 (1992). The developmental role of 5-HT in mammals can be understood through a series of papers on the effects of 5-HT on plasticity in Aplysia . This paper is particularly relevant in this respect because it offers a mechanism to explain how 5-HT could promote axon growth.

    CAS  PubMed  Google Scholar 

  120. Lieberman, J. et al. A decade of serotonin research: role of serotonin in treatment of psychosis. Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol. Psychiatry 44, 1099–1117 (1998).

    CAS  PubMed  Google Scholar 

  121. Lesch, K. P. & Mossner, R. Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol. Psychiatry 44, 179–192 (1998).

    CAS  PubMed  Google Scholar 

  122. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).

    CAS  PubMed  Google Scholar 

  123. Leboyer, M. et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol. Psychiatry 45, 158–163 (1999).

    CAS  PubMed  Google Scholar 

  124. Chugani, D. C. et al. Developmental changes in brain serotonin synthesis capacity in autistic and non autistic children. Ann. Neurol. 45, 287–295 (1999).

    CAS  PubMed  Google Scholar 

  125. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H. & van Oost, B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580 (1993). This study provided evidence that MAOA, a key enzyme in the degradation pathway of 5-HT, could have a role in social behaviour in humans. A single point mutation in the gene led to enhanced impulsive and aggressive behaviour in affected patients.

    CAS  PubMed  Google Scholar 

  126. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002). In the wake of the previous family case, this broader survey of MAOA gene polymorphisms underlined the intricacies of genotype and environment for determining the developmental role of 5-HT.

    CAS  PubMed  Google Scholar 

  127. Ding, Y. Q. et al. Lmx1b is essential for the development of serotonergic neurons. Nature Neurosci. 6, 933–938 (2003).

    CAS  PubMed  Google Scholar 

  128. Gross, C., Santarelli, L., Brunner, D., Zhuang, X. & Hen, R. Altered fear circuits in 5-HT1A receptor KO mice. Biol. Psychiatry 48, 1157–1163 (2000).

    CAS  PubMed  Google Scholar 

  129. Sibille, E., Pavlides, C., Benke, D. & Miklos, T. Genetic inactivation of the serotonin1A receptor in mice results in downregulation of major GABAA receptor a subunits, reduction of GABAA receptor binding, and benzodiazepine-resistant anxiety. J. Neurosci. 20, 2758–2765 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Boutrel, B., Monaca, C., Hen, R., Hamon, M. & Adrien, J. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice. J. Neurosci. 22, 4686–4692 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Brunner, D., Buhot, M. C., Hen, R. & Hofer, M. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav. Neurosci. 113, 587–601 (1999).

    CAS  PubMed  Google Scholar 

  132. Fiorica-Howells, E., Hen, R., Gingrich, J., Li, Z. & Gershon, M. D. 5-HT(2A) receptors: location and functional analysis in intestines of wild-type and 5-HT2A knockout mice. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G877–G893 (2002).

    CAS  PubMed  Google Scholar 

  133. Nebigil, C. G. et al. Ablation of serotonin 5-HT2B receptors in mice leads to abnormal cardiac structure and function. Circulation 103, 2973–2979 (2001).

    CAS  PubMed  Google Scholar 

  134. Heisler, L. K., Chu, H. M. & Tecott, L. H. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann. NY Acad. Sci. 861, 74–78 (1998).

    CAS  PubMed  Google Scholar 

  135. Heisler, L. K. et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl Acad. Sci. USA 95, 15049–15054 (2003).

    Google Scholar 

  136. Zeitz, K. P. et al. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci. 22, 1010–1019 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Compan, V. et al. Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 knockout mice. J. Neurosci. (in the press).

  138. Graihe, R. et al. Increased exploratory activity and altered response to LSD in the 5-HT5A receptor. Neuron 22, 581–591 (1999).

    Google Scholar 

  139. Hedlund, P. B. et al. No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc. Natl Acad. Sci. USA 100, 1375–1380 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Bengel, D. et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4- methylenedioxymethamphetamine ('Ecstasy') in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649–655 (1998).

    CAS  PubMed  Google Scholar 

  141. Persico, A. M. et al. Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J. Neurosci. 21, 6862–6873 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Grimsby, J. et al. Increased stress response and β-phenylethylamine in MAOB–deficient mice. Nature Genet. 17, 206–210 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

P.G., O.C. and L.M. are supported by the INSERM (Institut de la Santé et de la Recherche Médicale) and the CNRS (Centre National de la Recherche Scientifique). We are grateful to all our colleagues who generously shared with us their knockout mouse models and particularly to our long-standing collaborator I. Seif. We thank S. Marty for his critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patricia Gaspar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

LocusLink

5-HT1

5-HT2

5-HT3A

5-HT3B

5-HT4

5-HT5

5-HT6

5-HT7

Bdnf

Fgf4

Fgf8

Gata3

Gdnf

Lmx1

Maoa

Maob

Mas1

Nkx2.2

Pet1

Sert

Shh

Tph1

Tph2

Vmat2

Glossary

TRYPTOPHAN HYDROXYLASE

(Tph1, Tph2). The rate-limiting enzyme for serotonin (5-HT) synthesis. Tph converts tryptophan into 5-hydroxytryptophan. The essential amino acid tryptophan is taken up into the cells by a nonspecific amino-acid transporter. Two Tph genes have been identified in mammals, Tph1 and Tph2, and are expressed in the periphery and in the raphe nuclei, respectively.

AROMATIC AMINO ACID DECARBOXYLASE

(AADC). Converts 5-hydroxytryptophan into 5-HT. This enzyme is not specific to the serotonergic system as it is also used to decarboxylate dopamine and histidine.

SEROTONIN (5-HT) TRANSPORTER

(Sert). This plasma membrane transporter allows a highly efficient capture of 5-HT into cells (affinity 10−7 M). It belongs to the family of Na+- and Cl-coupled transporters, with 12 transmembrane domains. Energy for this active uptake is generated by the Na+-K+ ATPase. Only one gene has been identified. Inhibitors of Sert, SSRIs, are widely prescribed as antidepressants.

VESICULAR MONOAMINE TRANSPORTER

(Vmat2, Vmat1). A synaptic vesicle protein that transports monoamines (5-HT, dopamine, noradrenaline and histamine) from the cytoplasm into vesicles, using a proton gradient. Two isoforms have been cloned, Vmat2 in the CNS, and Vmat1 in the periphery. Inhibitors of Vmat have been used as amine depleting agents for the treatment of hypertension and can cause depression as a side effect.

MONOAMINE OXIDASES

(Maoa, Maob). These are enzymes located in the outer mitochondrial membrane that de-aminate biogenic amines. Maoa is the most active subtype in 5-HT metabolism. Inhibitors of Maoa are potent antidepressants.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gaspar, P., Cases, O. & Maroteaux, L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4, 1002–1012 (2003). https://doi.org/10.1038/nrn1256

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1256

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing