Alexandre Bonnin - US grants

DESCRIPTION (provided by applicant): 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.

? DESCRIPTION (provided by applicant): Increasing numbers of pregnant women are prescribed selective serotonin (5-HT) reuptake inhibitor (SSRI) antidepressants to treat depression during pregnancy. SSRI treatment in early pregnancy has recently been associated with increased risk of adverse effects such as autism spectrum disorder (ASD) later in offspring life. Adverse effects are not avoided by foregoing therapy, as untreated depression and the associated maternal stress affect offspring neurological outcomes. Additionally, epidemiological studies cannot clearly separate medication from maternal disease effects on the developing offspring brain. The goal of this project is to dissociate mechanistically the short- and long-term effects of exposure to maternal stress and to SSRIs on fetal brain development and adult function using a mouse model. The first aim determines the specific parameters of fetal brain exposure to SSRIs and their metabolites, including influence of gestational age, dosage, duration of exposure and identity of the drug. Experiments proposed in this aim take advantage of a newly developed methodology for studying placental drug transport; this unique expertise will permit us to measure bi-directional drug transport between mother and fetus, as well as placental drug accumulation and metabolism at different stages of pregnancy. The second aim investigates the effect of prenatal exposure to maternal stress and commonly used SSRIs (alone and in combination) on fetal brain structure, neurochemistry and serotonergic and thalamocortical neuronal pathway formation. Experiments combine new high-resolution whole fetal brain diffusion magnetic resonance imaging (in collaboration with Dr Irina Burd at Johns Hopkins University), biochemistry and immunohistochemistry to investigate the effects of timing and duration of exposure on structure and neuronal circuit formation in situ. The third aim determines the long-term effects of maternal stress and SSRI exposure at different times of gestation on adult offspring brain function. The proposed experiments use recent advances in highly time-resolved microdialysis (in collaboration with Dr Anne Andrews at UCLA) to determine changes in basal and stimulated extracellular 5-HT levels in ventral hippocampus in awake adult male and female offspring. Relevance to public health: The proposed studies address an urgent need for the investigation of fetal developmental risks that stem from maternal stress/depression and/or its pharmacological treatment during pregnancy, while further defining prenatal sensitive periods that influence complex biological interactions between the mother, placenta and fetal brain. In the long term this research is expected to lead to improved risk assessment, and to help to develop safer therapeutic strategies for pregnant women and their offspring.