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Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6

Molecular Psychiatry volume 14, pages 280–290 (2009)Cite this article

Abstract

The discovery that a common polymorphism (5-HTTLPR, short variant) in the human serotonin transporter gene (SLC6A4) can influence personality traits and increase the risk for depression in adulthood has led to the hypothesis that a relative increase in the extracellular levels of serotonin (5-HT) during development could be critical for the establishment of brain circuits. Consistent with this idea, a large body of data demonstrate that 5-HT is a strong neurodevelopmental signal that can modulate a wide variety of cellular processes. In humans, serotonergic fibers appear in the developing cortex as early as the 10th gestational week, a period of intense neuronal migration. In this study we hypothesized that an excess of 5-HT could affect embryonic cortical interneuron migration. Using time-lapse videometry to monitor the migration of interneurons in embryonic mouse cortical slices, we discovered that the application of 5-HT decreased interneuron migration in a reversible and dose-dependent manner. We next found that 5-HT6 receptors were expressed in cortical interneurons and that 5-HT6 receptor activation decreased interneuron migration, whereas 5-HT6 receptor blockade prevented the migratory effects induced by 5-HT. Finally, we observed that interneurons were abnormally distributed in the cerebral cortex of serotonin transporter gene (Slc6a4) knockout mice that have high levels of extracellular 5-HT. These results shed new light on the neurodevelopmental alterations caused by an excess of 5-HT during the embryonic period and contribute to a better understanding of the cellular processes that could be modulated by genetically controlled differences in human 5-HT homeostasis.

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Acknowledgements

We thank C Aubry, B Pastori, P Marin and B King for technical assistance. This work was supported by a Swiss National Foundation grant 3100A0-116496 and De Reuter Foundation to A.G.D. and Swiss National Foundation grant 3100A0-116496, the Eagle Foundation and by the European Community Grant Promemoria No. 512012-2005 to J.Z.K.

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Authors and Affiliations

  1. Department of Adult Psychiatry, University Hospital of Geneva, Geneva, Switzerland

    O Riccio, C Walzer, P Vallet & A G Dayer

  2. Department of Fundamental Neurosciences, University of Geneva Medical School, Geneva, Switzerland

    O Riccio, G Potter, L Vutskits, J Z Kiss & A G Dayer

  3. Department of Gene Technology and Developmental Neurobiology, Institute of Experimental Medicine, Budapest, Hungary

    G Szabó

  4. Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland

    L Vutskits

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  1. O Riccio
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Correspondence to A G Dayer.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Riccio, O., Potter, G., Walzer, C. et al. Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6. Mol Psychiatry 14, 280–290 (2009). https://doi.org/10.1038/mp.2008.89

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