Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology


J Psychiatry Neurosci 2015;40(1):5-18

Linda Booij, PhD; Richard E. Tremblay, PhD; Moshe Szyf, PhD; Chawki Benkelfat, MD, DERBH


Background: Despite more than 60 years of research in the role of serotonin (5-HT) in psychopathology, many questions still remain. From a developmental perspective, studies have provided more insight into how 5-HT dysfunctions acquired in utero or early in life may modulate brain development. This paper discusses the relevance of the developmental role of 5-HT for the understanding of psychopathology. We review developmental milestones of the 5-HT system, how genetic and environmental 5-HT disturbances could affect brain development and the potential role of DNA methylation in 5-HT genes for brain development.

Methods: Studies were identified using common databases (e.g., PubMed, Google Scholar) and reference lists.

Results: Despite the widely supported view that the 5-HT system matures in early life, different 5-HT receptors, proteins and enzymes have different developmental patterns, and development is brain region–specific. A disruption in 5-HT homeostasis during development may lead to structural and functional changes in brain circuits that modulate emotional stress responses, including subcortical limbic and (pre)frontal areas. This may result in a predisposition to psychopathology. DNA methylation might be one of the underlying physiologic mechanisms.

Limitations: There is a need for prospective studies. The impact of stressors during adolescence on the 5-HT system is understudied. Questions regarding efficacy of drugs acting on 5-HT still remain.

Conclusion: A multidisciplinary and longitudinal approach in designing studies on the role of 5-HT in psychopathology might help to bring us closer to the understanding of the role of 5-HT in psychopathology.

Submitted Apr. 6, 2014; Revised July 9, 2014; Accepted July 23, 2014; Early-released Oct. 7, 2014.

Acknowledgements: L. Booij is supported by a New Investigator Award from the Canadian Institutes of Health Research (CIHR). L. Booij thanks the Canadian College of Neuropsychopharmacology (CCNP) for the CCNP 2013 Young Investigator Award, which involved the writing of this invited manuscript. The authors thank J-B. Ng Man Sun, for assistance with the figures.

Affiliations: Sainte-Justine Hospital Research Centre & University of Montreal, Montréal, Que., Canada (Booij, Tremblay); Department of Psychology and Psychiatry, Queen’s University, Kingston, Ont., Canada (Booij); Department of Psychiatry (Booij, Benkelfat), Department of Pharmacology and Therapeutics (Szyf), McGill University, Montréal, Que., Canada; Department of Psychiatry (Booij), Departments of Psychology and Pediatrics (Tremblay), University of Montréal, Montréal, Que., Canada; School of Public Health and Population Sciences, University College Dublin, Dublin, Ireland (Tremblay).

Competing interests: M. Szyf holds the GlaxoSmithKline–Canadian Institutes of Health Research professorship in pharmacology. No other competing interests declared.

Contributors: L. Booij and C. Benkelfat designed the review. All authors reviewed and interpreted parts or all of the literature. L. Booij wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140099

Correspondence to: Booij, Departments of Psychology and Psychiatry, Queen’s University, 62 Arch St., Kingston ON K7L 3N6; or