During gestation, the excitatory neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) directs synapse formation and pruning in fetal brain circuits responsible for shaping social behavior. This course of development continues to unfold after birth and with social stimulation, both in juvenile mice and in infants. The 5-HT neurotransmitter system, including its transporters and receptors, are among the earliest to appear in the brain during embryonic development. Critically, this occurs even before the fetal brain has neurons capable of producing 5-HT on their own. In the placenta and/or in the fetal brain, it is maternal tryptophan (TRP) that is used to synthesize the majority of the 5-HT involved in this early signaling process. Maternal metabolic demand for 5-HT typically can accommodate fetal TRP demands, however if maternal 5-HT and TRP demand is elevated, fetal TRP and 5-HT deficiency may set the stage for development of social behavior deficiency in her offspring. Such circumstances might include, for example, expectant mothers with gene polymorphisms resulting in deficient serotonin transporter (SERT) expression and/or function, or in mothers who need to take selective serotonin-reuptake inhibiting (SSRI) antidepressants. Under these conditions, maternal neuronal 5- HT stores are not replenished as readily SERT-mediated 5-HT recycling, and maternal demand for TRP to synthesize 5-HT de novo may compete with fetal needs for brain development. In adult mice we discovered that enhanced TRP diet improved the social behaviors of socially impaired strains and genotypes, while TRP depletion increased serum corticosterone (mouse equivalent of the stress hormone cortisol) and reduced SERT density. This project will compare the effects of dietary TRP depletion (by 50-75%) or enhancement (by 1%) during gestation and lactation on social behavior and several key functional markers of the 5-HT system in young adult offspring of SSRI-treated and control dams. SERT -/- mice, with innately low social behavior, and SERT +/- and SERT +/+ dams and offspring that are usually gregarious will be used. During pregnancy and lactation, maternal TRP levels will be monitored. Upon reaching early adulthood (postnatal days 60-65) offspring will be tested for sociability in three-chamber tests, followed by comparison of 5-HT-dependent serum oxytocin and corticosterone levels. After behavioral testing, brains from young adult offspring mice will be examined for the density of gene and protein expression of 5-HT transporters and 5-HT1A, 5-HT1B, and 5-HT2 receptors, all of which are key regulators of 5-HT neurotransmission. Finally, and most critically, mouse brain tissue will be analyzed for TRP and 5-HT levels and their metabolic turnover through HPLC measurements. Maternal dietary TRP enhancement should increase 5-HT levels in offspring brains and improve social behavior, 5-HT receptor and transporter density may increase, stress response (cortisol levels) should be blunted and increases in circulating oxytocin levels are anticipated in young adult offspring. The opposite effects are anticipated with TRP depletion, including increased aggression.
Maternal tryptophan intake is crucial to maintaining proper levels of the neurotransmitter serotonin in the fetal brain, particularly under conditions where competing demands for this essential amino acid are high. In this study maternal dietary tryptophan availability will be manipulated in pregnant serotonin transporter knock-out, heterozygous and wild-type mice, in conjunction with antidepressant administration to assess their individual impacts and interactions on serotonin metabolism, neuroregulatory proteins in brain, serum corticosterone and oxytocin levels and social behaviors in their adult offspring. The study findings may inform development of appropriate maternal biomarkers, and complimentary dietary and pharmaceutical interventions to prevent or reduce the severity of autism and related disorders.
| Garbarino, Valentina R; Gilman, T Lee; Daws, Lynette C et al. (2018) Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder. Pharmacol Res : |
| Schultz, Stephen T; Gould, Georgianna G (2016) Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism Open Access 6: |
