. An estimated 1 in 68 children is diagnosed with autism spectrum disorder (ASD), a debilitating neurodevelopmental condition associated with behavioral deficits and abnormal neural connectivity2, 4. Immune events during pregnancy are increasingly implicated in ASD etiology; for example, children who are born to mothers who were diagnosed with an infection during pregnancy are at higher risk of developing ASD. We have been modeling the effects of midgestational immune events in mice at a time window that coincides with the development of cortical structures implicated in ASD. In particular, we have studied the birth of cortical projection neurons that form long-range connections in the brain5, 6. Maternal immune responses induced at mouse embryonic day 12.5 (E12.5) selectively impact the production of callosal projection neurons. Preliminary data suggests that mid-gestational maternal immune activation (MIA) contributes to an ASD phenotype by impinging on radial glial cell-mediated cortical patterning and the specification of cortical projection neuron subtypes1. The central nervous system (CNS) originates in a single layer of specialized columnar epithelium called radial glia. Radial glia are multipotent stem cells that sequentially give rise to all neurons, astrocytes, and oligodendrocytes of the CNS. We have found that radial glia self-renewal is altered following MIA and that key signaling pathways are disrupted. Interestingly, several of the pathways disrupted by MIA overlap with the molecular pathways influenced by several autism risk genes. It is not known how ASD risk genes mediate the effects of MIA, despite evidence that ASD risk genes worsen social interaction in MIA-exposed mice and increase the likelihood of developing ASD following MIA in humans7, 8. The interaction of MIA with a risk gene may produce unique effects that are not observed by studying each risk in isolation. Furthermore, it is known that gene-environment interaction is key to ASD onset, as there is no known single gene or environmental cause of autism. Here we propose to test whether genetic risk and immune risk generate convergent or synergistic effects on radial glial patterning at the level of the transcriptome.

Public Health Relevance

. Autism Spectrum Disorder (ASD) affects an estimated 1 in 68 children born in the United States, and each child costs $2.2 million dollars to support across their lifetime2, 3. Although ASD emerges from a combination of environmental and genetic risks, the specific causes of the disorder are unknown. This research will explore gene-environment interaction in the developing brain to better understand the effects of ASD risk factors, and to identify preventative therapies for pregnant women.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Van'T Veer, Ashlee V
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Stanford University
Schools of Medicine
United States
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