Deciphering the influences of fetal programming on adult mental disorders causality depends on the identification of specific molecular pathways involved in their etiology. New insights will provide the means for reducing developmentally based disorder risk, and new therapeutic targets for treatments in adulthood. For example, our recent discovery of maternal–placental–fetal interactions that may influence brain development leads to new hypotheses regarding the mechanisms by which fetal programming of adult mental disorders may occur. A tryptophan (the precursor of serotonin—5-HT) metabolic pathway in the placenta (Bonnin et al, 2011) reflects the potential importance of extra-embryonically derived 5-HT in modulating developmental processes such as brain circuit wiring, thus affecting long-term brain function. This concept is consistent with classic genetic (5-HT1A knockout) and pharmacological (SSRI exposure) studies showing that disruption of 5-HT signaling transiently, during a restricted period of pre- or postnatal development, results in long-term behavioral abnormalities, such as increased anxiety in adulthood (Ansorge et al, 2008; Oberlander et al, 2009). Because many 5-HT receptors are expressed early and in complex temporal and spatial patterns during brain development (Bonnin et al, 2006), the full extent of the mechanisms through which disruption of 5-HT signaling leads to adult phenotypes is not yet understood. One possible route through which it could occur is the disruption of the modulatory activity of 5-HT signaling on fetal forebrain wiring. This was demonstrated in vitro via the modulation of netrin-1 axon guidance activity by 5-HT, and in vivo by simultaneous, targeted disruption of two 5-HT receptors (5-HT1B/1D) (Bonnin et al, 2007). Altered 5-HT signaling in the forebrain could preferentially influence wiring in this brain region in utero (Bonnin et al, 2007; Bonnin et al, 2011), ultimately leading to long-term dysfunction of circuits underlying mood and emotion. Control of 5-HT signaling, through the number and/or type of 5-HT receptors activated, may thus be critical for normal brain development.

During pregnancy, altered availability of 5-HT itself also may lead to abnormal signaling in the fetal brain. The newly discovered placenta-derived 5-HT accumulates in the fetal forebrain (but not the hindbrain; (Bonnin et al, 2011)). The period during which placental 5-HT reaches the forebrain in the mouse corresponds to the first and early second trimesters in the human, prenatal periods of neuronal migration, and initial circuit formation that are associated with greater risk for mental illnesses due to maternal perturbations. Thus, like other placenta-derived molecules (eg, growth factors), placental 5-HT output could be affected by both genetic (the embryo and placenta are genetically identical) and environmental disturbances that are known to increase risk for mental illnesses. In fact, altered tryptophan metabolism during pregnancy in mice has long-term functional consequences in the offspring, and has been implicated in increasing the risk for schizophrenia, bipolar disorder, and autism in humans (Miller et al, 2009). Although long-term follow-up studies are needed, prenatal exposure to SSRI antidepressants induces an array of disturbances in childhood. It is hypothesized that maternally ingested SSRIs cross the placental barrier and directly impact fetal brain development. However, as the serotonin transporter (SERT; Slc6a4) is also highly expressed in the placenta, SSRIs may impact placental function and have indirect effects on fetal development. The SSRIs impact on placental physiology at different stages of gestation is currently under investigation, using the newly developed ex vivo dual perfusion system for the mouse placenta (Bonnin et al, 2011).

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