Research to Address the Heterogeneity in Autism Spectrum Disorders (ASD) Project title: An ex-vivo placental perfusion system to study materno-fetal biology. This grant will focus on developing and validating a model system to examine the effects of alterations in materno-fetal interactions on fetal brain development. We propose that the impact of maternal immune challenges and stressors on fetal brain development is a direct consequence of altered materno-fetal interactions taking place in the placenta. Circulating maternal tryptophan metabolism in the placenta is known to be required for protecting the fetus from maternal immunity. Our preliminary results suggest that, during an early critical period of gestation, an alternative pathway of tryptophan placental metabolism also provides serotonin to the fetal circulation and therefore may be critical for normal fetal brain wiring. Advancing a new ex vivo dual perfusion model system proposed here will enable us to test the possibility that maternal immune challenges directly impact multiple placental metabolic pathways for Trp disrupting fetal supply of 5-HT and ultimately brain wiring in utero. Since placental metabolic functions change during pregnancy, we hypothesize that the degree to which maternal factors impact fetal brain development will depend on a combination of timing, nature of the challenges and also genetic susceptibility of the mother and offspring. Our ex vivo model system will provide a unique way to dissect the effect of each factor on tryptophan placental metabolism and subsequently its contribution to impacting neurobiological functions relevant to ASD such as fetal brain circuits formation. The use of mouse placentas will enable us to test the impact of altered placental metabolism in a wide array of genetic models relevant to ASD and at different stages of gestation. This is a critical advance, as it provides unique opportunities to determine how maternally derived neurotransmitters, cytokines, hormones and drugs impact the development of 5HT-relevant and other circuits that have been implicated in ASD.

Public Health Relevance

Maternal-fetal interactions during the prenatal period are essential for brain development in the child. Maternal illness which increases the risk for neuropsychiatric disorders, including ASD, may impair these interactions. We propose to design and implement a new technology that will provide unique opportunities to determine how maternally derived molecules such as neurotransmitters, cytokines, hormones and drugs reach the fetal brain and impact the development of circuits that have been implicated in ASD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1-ERB-C (A1))
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Vitkovic, Ljubisa
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University of Southern California
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
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Goeden, Nick; Velasquez, Juan; Arnold, Kathryn A et al. (2016) Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. J Neurosci 36:6041-9
Goeden, Nick; Bonnin, Alexandre (2013) Ex vivo perfusion of mid-to-late-gestation mouse placenta for maternal-fetal interaction studies during pregnancy. Nat Protoc 8:66-74
van Kleef, Esmee S B; Gaspar, Patricia; Bonnin, Alexandre (2012) Insights into the complex influence of 5-HT signaling on thalamocortical axonal system development. Eur J Neurosci 35:1563-72
Bonnin, Alexandre; Levitt, Pat (2012) Placental source for 5-HT that tunes fetal brain development. Neuropsychopharmacology 37:299-300
Bonnin, A; Levitt, P (2011) Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience 197:1-7
Bonnin, Alexandre; Goeden, Nick; Chen, Kevin et al. (2011) A transient placental source of serotonin for the fetal forebrain. Nature 472:347-50