Abstract
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.
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