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Lack of Serotonin Transporter Alters BDNF Expression in the Rat Brain During Early Postnatal Development

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Abstract

It is well established that alterations of the serotoninergic system may contribute to the pathophysiology of mood disorders. Accordingly, it has been demonstrated that genetic deletion of the serotonin transporter (SERT) in rodents leads to an anxious and depressive phenotype, which is also associated with reduced neuronal plasticity. Indeed, we have demonstrated that adult SERT−/− animals show decreased brain-derived neurotrophic factor (BDNF) expression, as well as reduced levels of transcription factor regulating the neurotrophin transcription. While these changes may represent long-term consequences of impaired function of the transporter during development, no information exists with respect to the developmental profile of such changes. Using SERT−/− rats at different ages, we found that the impairment in neuroplasticity originates early in development and worsens during the first 3 weeks of life. Indeed, we observed that BDNF expression was reduced at birth and that the magnitude of these changes became more pronounced starting from PND21, being sustained by epigenetic mechanisms as well as alterations in the expression of specific transcription factors, including Npas4 and CaRF. These results suggest that an impairment of SERT may affect BDNF expression throughout postnatal development. These early changes may increase stress susceptibility during critical windows of brain maturation, which may eventually lead to the heightened predisposition to mood disorders found in individual carrying genetic variants of the serotonin transporter.

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Acknowledgments

This publication was made possible by grants to M.A. Riva from Regione Lombardia (Markdep) and from an European Research Projects on Mental Disorders (ERA-NET NEURON 2010), as well as by grants from The Netherlands Organisation for Scientific Research (NWO, grant # 86410003), to J. Homberg.

Conflict of Interest

The authors Calabrese F, Guidotti G, Middelman A, and Homberg J have no financial interest or potential conflict of interest. Racagni G has received compensation as speaker/consultant for Eli Lilly, InnovaPharma, Roche, Servier. Riva MA has received compensation as speaker/consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Roche, Servier, Takeda.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita’ degli Studi di Milano, Milan, Italy

    Francesca Calabrese, Gianluigi Guidotti, Giorgio Racagni & Marco A. Riva

  2. Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy

    Giorgio Racagni & Marco A. Riva

  3. Donders Institute for Brain, Cognition, and Behaviour, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Anthonieke Middelman & Judith Homberg

  4. Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy

    Marco A. Riva

  5. I.R.C.C.S. San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

    Giorgio Racagni

Authors
  1. Francesca Calabrese
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  2. Gianluigi Guidotti
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  3. Anthonieke Middelman
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  4. Giorgio Racagni
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  5. Judith Homberg
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  6. Marco A. Riva
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Correspondence to Marco A. Riva.

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Calabrese, F., Guidotti, G., Middelman, A. et al. Lack of Serotonin Transporter Alters BDNF Expression in the Rat Brain During Early Postnatal Development. Mol Neurobiol 48, 244–256 (2013). https://doi.org/10.1007/s12035-013-8449-z

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  • DOI: https://doi.org/10.1007/s12035-013-8449-z

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