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Estes and McAllister (2015) doi: 10.1126/science.aag3194
Schizophrenia (SZ) and autism spectrum disorder (ASD) are complex diseases caused by a combination of genetic changes and environmental factors during early development. Despite the prevalence of these disorders, current treatments are mostly ineffective for SZ and non-existent for ASD. In addition to hundreds of genes linked to these disorders, maternal infection has also been found to increase risk for ASD and SZ in offspring. Because maternal SARS-CoV-2 infection appears to have a similar outcome, the need for new strategies to treat these disorders and prevent the effects of maternal infection in offspring could not be more urgent.
Mechanisms underlying the effect of MIA in altering brain development and behavior in offspring
Using a validated mouse model of maternal infection, we have shown that maternal immune activation (MIA) leads to long-lasting changes in immune molecules in the brains of offspring, including region- and age- specific changes in cytokine protein levels throughout postnatal development (Garay et al. 2013). In addition, cortical neurons from newborn MIA offspring exhibit a profound deficit in their ability to form synapses that requires MIA-induced elevations in MHCI on neurons (Elmer et al. 2013). Through a collaboration with the Nord lab at UC Davis, we have also identified several molecular pathways that are altered over time in the brain of MIA offspring during prenatal development. An acute response (hypoxia, immune signaling, and angiogenesis) was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5, when proliferation was decreased and gliogenesis was enhanced (Canales et al. 2020).
Ongoing projects aim to:
(i) identify the molecular mechanisms that underlie these changes both pre- and postnatally
(ii) determine if MIA alters similar pathways in the brains of mice and NHP offspring
(iii) identify the role of dopamine dysregulation in aberrant behaviors in offspring
Identifying factors that confer susceptibility and resilience to MIA
Recently, we have identified two factors that predict susceptibility and resilience of offspring to MIA using the mouse model, allowing us to study why some pregnancies may be resilient to MIA and how MIA can lead to a wide range of distinct phenotypic outcomes in offspring. Understanding susceptibility and resilience to MIA is especially relevant for this risk factor since most human pregnancies are resilient to maternal infection and there is no biomarker to indicate which are susceptible. Moreover, those pregnancies that are susceptible lead to a range of neurodevelopmental and psychiatric illness in offspring. Our ability to predict which groups will be susceptible and manifest specific phenotypic outcomes provides an unprecedented opportunity to identify fundamental maternal immune and neurodevelopmental molecular and circuit-based mechanisms that cut across current diagnostic categories as outlined in the Research Domain Criteria (RDoC). If successful, our work may identify novel approaches to determine which pregnancies will be susceptible to MIA, as well as strategies to treat and/or prevent neurodevelopmental and/or psychiatric disorders in offspring. For more information see: UC Davis NIMH Conte Center.
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