The incidence of many neurodevelopmental disorders including autism, schizophrenia, and cerebral palsy are considerably higher in males than females. In the case of autism spectrum disorder (ASD), recent estimates indicate that autism is 4 to 5 times more prevalent in males than females. The reason(s) for male vulnerability and female protection in autism currently remain poorly understood. Improved understanding of the molecular and cellular factors that underlie sex-bias in neurodevelopmental disorders will provide important new insights into the etiologies of these complex disorders and will ultimately help to reveal much-needed biomarkers and therapeutic targets for neurodevelopmental disease. In our preliminary studies, we have found that altering the extent of maternal immune activation (MIA) influences development of autism-related behavioral abnormalities in a sex-specific manner. More specifically, we demonstrate that low levels of gestational inflammation promotes the development of autism-related phenotypes in male but not female offspring. In contrast, enhancing MIA above a threshold promotes female-specific induction of neurodevelopmental disorders and fetal reabsorption of male offspring. Interestingly, in our male-biased model of neurodevelopmental disease, we observe that microglial pathways are hyperactivated in male offspring and not females. Moreover, we find that anti-CSF1R knockdown of microglia and other myeloid cells during early gestation provides substantial protection against the development of behavioral abnormalities in the MIA model. Microglia are tissue-resident macrophages of the central nervous system (CNS) that aid in the clearance of debris and pathogens, and also have been reported to participate in synaptic pruning, axon guidance, and neurogenesis. Recent studies have begun to reveal sex-based differences in microglia activity that can contribute to distinct disease outcomes in the adult brain. In contrast, little is currently known in regard to how sex modulates microglia responses in neurodevelopmental disorders. Given our preliminary findings, we hypothesize that MIA results in sex-specific alterations in microglia activities that can affect neurodevelopment. For this exploratory project, we propose two aims to define how sex shapes microglia dynamics and function (Aim 1), and gene expression (Aim 2) in a neurodevelopmental disorder model driven by MIA. Completion of the proposed studies will break new ground in our understanding of how gestational exposure to inflammation can alter microglia responses in a sex- specific manner and will provide new insights into the underpinnings of neurodevelopmental disorders.

Public Health Relevance

While the etiology of autism remains poorly understood, sex-specific effects have been well described throughout the literature with current estimates indicating that autism is 4 to 5 times more prevalent in males than females. In our preliminary studies using a murine model of maternal immune activation (MIA) associated neurodevelopmental disease, we demonstrate that we can selectively induce autism-related phenotypes in male but not female offspring, and that microglia ablation with anti-CSF1R treatment during early gestation provides substantial protection against the development of neurodevelopmental disorders. Following up on these findings and our other preliminary data demonstrating sex-specific alterations in microglia, we will interrogate how sex influences microglia activity in response to MIA, with the goal of gaining new insights into the molecular and cellular underpinnings of neurodevelopmental disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Tonelli, Leonardo H
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University of Virginia
Schools of Medicine
United States
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