DescrizioneStudies in recent years have suggested that maternal and extraembryonic sources of serotonin, such as placenta, play pivotal roles in embryonic brain development. However, the identity of serotonergic system components and cell types expressing serotonergic genes during development, as well as mechanisms of serotonin transport to the embryo remain controversial (Bonnin et al., Nature. 2011; 472(7343):347-50; Kliman et al., Endocrinology. 2018;159(4):1609-1629). The aim of this project is to evaluate the contribution of extraembryonic sources of serotonin to PFC development and to dissect the involved cellular and molecular components. Since such an approach is not possible in humans, we will use mouse models deficient in genes encoding the serotonin synthesizing enzymes, TPH1 (Walther et al. Science 2003;299:76) and TPH2 (Alenina et al. Proc Natl Acad Sci USA 2009;106:10332-7), and the monoamine transporters, SERT and OCT3, to clarify if these proteins contribute to the supplementation of the fetus with serotonin in the absence of own serotonin production and what is their role in brain development. We will investigate the effect of maternal and placental SERT, OCT3, TPH1 and TPH2 depletion on the serotonin levels in placenta and different parts of the embryonic brain before the onset of Tph2 expression at embyronic day (E) 10-11; after the birth of serotonergic neurons (E12-14) and upon serotonergic innervation of the forebrain (E15-16) and on serotonergic-innervation pattern at later stages of embryogenesis.

Serotonin is a neurotransmitter playing a crucial in the onset and treatment of neuropsychiatric disorders. Most of the drugs currently used in psychiatry target serotonin (neuro)transmission. However, it is becoming increasingly clear that the efficacy of these drugs is suboptimal. As a result, the prevalence and burden of these disorders remain high. A new wave of research revealed that serotonin plays important role in neurodevelopment.Changes in serotonin levels lead to changes in developmental processes with consequences for the serotonin system and beyond. This makes it plausible that the origins of these disorders do not per se lie in disturbed serotonin neurotransmission, but rather in serotonin-mediated neurodevelopmental changes. This would require a radical different view on disease burden reduction.We hypothesize that it are the serotonin-mediated non-serotonergic downstream changes in neurodevelopment that are at the basis of serotonin-related neuropsychiatric disorders.