Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6

Abstract

The discovery that a common polymorphism (5-HTTLPR, short variant) in the human serotonin transporter gene (SLC6A4) can influence personality traits and increase the risk for depression in adulthood has led to the hypothesis that a relative increase in the extracellular levels of serotonin (5-HT) during development could be critical for the establishment of brain circuits. Consistent with this idea, a large body of data demonstrate that 5-HT is a strong neurodevelopmental signal that can modulate a wide variety of cellular processes. In humans, serotonergic fibers appear in the developing cortex as early as the 10th gestational week, a period of intense neuronal migration. In this study we hypothesized that an excess of 5-HT could affect embryonic cortical interneuron migration. Using time-lapse videometry to monitor the migration of interneurons in embryonic mouse cortical slices, we discovered that the application of 5-HT decreased interneuron migration in a reversible and dose-dependent manner. We next found that 5-HT6 receptors were expressed in cortical interneurons and that 5-HT6 receptor activation decreased interneuron migration, whereas 5-HT6 receptor blockade prevented the migratory effects induced by 5-HT. Finally, we observed that interneurons were abnormally distributed in the cerebral cortex of serotonin transporter gene (Slc6a4) knockout mice that have high levels of extracellular 5-HT. These results shed new light on the neurodevelopmental alterations caused by an excess of 5-HT during the embryonic period and contribute to a better understanding of the cellular processes that could be modulated by genetically controlled differences in human 5-HT homeostasis.

Serotonin induces the migration of PC12 cells via the serotonin receptor 6/cAMP/ERK pathway

“…Depletion of 5-HT by injection of DL-P-chlorophenylalanine (PCPA, an inhibitor of 5-HT synthesis) during the E12-E17 stage arrested migration and disorganized the positioning of cortical neurons (7), suggesting a positive effect of 5-HT on migration. By contrast, cortical slices exposed to high doses of 5-HT (100-400 µM) arrested the migration of GABergic neurons (8,9). Although findings of those studies reported negative effects of 5-HT, the concentration of 5-HT was considerably higher than that of another study focusing on the prenatal cortex (100-200 fmol/mg) (7).…”

“…A number of studies have indicated that 5-HT affects proliferation of neural cells (7,(21)(22)(23) as well as neurite outgrowth (17,(24)(25)(26), however, its effect on neural migration remains to be clarified. Findings of previous studies suggest 5-HT affects cortical neuron migration during prenatal development (7)(8)(9)13). Depletion of 5-HT by injection of DL-P-chlorophenylalanine (PCPA, an inhibitor of 5-HT synthesis) during the E12-E17 stage arrested migration and disorganized the positioning of cortical neurons (7), suggesting a positive effect of 5-HT on migration.…”

“…By contrast, cortical slices exposed to high doses of 5-HT (100-400 µM) inhibited the migration of GABergic neurons. The arrested migration was recovered by application of the 5-HT 6 antagonist, SB258585 (8,9). However, the association between 5-HT dose and its effect on migration remains to be elucidated.…”

The Placenta as a Mediator of Stress Effects on Neurodevelopmental Reprogramming

“…As these cells reside between the maternal and fetal vasculature, such changes in transport would increase their intrauterine availability, especially that of serotonin, which is synthesized in maternal, placental, and fetal compartments (Bonnin and Levitt, 2011;Nguyen et al, 1999;Verhaagh et al, 2001). Subsequent fetal overexposure may have deleterious effects on brain development, where, eg, serotonin excess impaired embryonic cortical interneuron migration in mice (Riccio et al, 2009;Velasquez et al, 2013). Serotonin, a potent vasoconstrictor, also elevates vascular resistance and reduces utero-placental blood flow, a mechanism thought to underlie hypertension in preeclampsia and gestational diabetes (Bolte et al, 2001;Li et al, 2014).…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…(d) Gamma-aminobutyric acid and interneurons Morphogenic effects of 5-HT impact migration, differentiation and survival of GABAergic interneurons [80 -82] and 5-HT influences GABAergic cell migration via 5-HT6 receptors during late embryonic stages [89], thus assisting their integration into cortical networks [90]. The BLA is fundamentally involved in the regulation of fear and anxiety [91] and is densely innervated by serotonergic fibres from the DR nucleus [92].…”