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

Abstract

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.

Fig. 1

Overview of key findings in serotonin (5-HT) research over the past 65 years. SSRIs = selective serotonin reuptake inhibitors.

Fig. 2

Overview of the common serotonin (5-HT) diathesis-stress model of psychopathology. E = environment; G = gene.

Fig. 3

Timing of first expression of serotonin (5-HT) proteins, receptors and enzymes in the brain, including tryptophan hydroxylase-2 (TPH₂),, 5-HT transporter (SERT),, monoamine oxidase-A (MAOA),, 5-HT_1A receptor,, 5-HT_2A receptor and TPH₁. E = embryonic day; GW = gestational week; P = postnatal day.

Fig. 4

Timing of stabilization of serotonin (5-HT) proteins, receptors and enzymes in the brain, including tryptophan hydroxylase-2 (TPH₂),,, serotonin transporter (SERT),, monoamine oxidase-A (MAOA),, 5-HT_1A receptor,,, 5-HT_2A receptor, and TPH₁. P = postnatal day. *Published research indicates that the exact timing of stabilization depends on brain region. The number in the table reflects the approximate timing of stabilization across all investigated brain regions.

Fig. 5

Neurodevelopmental stress-diathesis model of psychopathology. 5-HT = serotonin; E = environment; G = gene.