Project Summary: Neurodevelopmental disorders such as autism and intellectual disability affect 14% of American children and over 50 million people world-wide. Pharmacological therapies for treating these disorders are virtually non- existent in large part due to our limited understanding of the neural circuit wiring deficits that underlie their diverse and nuanced symptoms. While it has been well-established that neurodevelopmental disorders emerge through a complex interplay of genetics (nature) and environmental factors (nurture), the majority of research into these conditions has focused on specific genetic mutations underlying rare subsets of disorders, leaving the environmental factors that affect a much wider array of these conditions poorly understood. To alleviate the suffering of as many individuals as possible, we will address this major gap in knowledge by defining the environmental factors that exacerbate neurodevelopmental dysfunction. Our approach is based upon mounting clinical and experimental evidence that impairments in interactions between the immune system and the brain drive neuropathology, an unexpected finding given that the immune and nervous systems were classically considered to be distinct biological domains. The central hypothesis underlying the proposed work is that a specialized class of brain-resident immune cells called microglia play a critical role in coordinating a late stage of circuit development that is thought to go awry in neuropathological states: the sensory experience-dependent refinement of developing synapses. If so, the disruption of microglial function in experience-dependent refinement may be a core feature of neurodevelopmental disorders rendering microglia a promising target for treatment, particularly because experience-dependent refinement represents a state of heightened plasticity when the brain may be particularly receptive to therapeutic intervention. Harnessing the unique advantages of the visual circuitry of the mouse as a model system, we will merge two-photon imaging of microglia and synapses in the brains of live, awake mice with single-cell genomics and CRISPR-based screens to define the roles of microglia in experience-dependent refinement. In parallel, we will utilize the maternal immune activation mouse model to identify specific mechanisms of refinement that are likely to be disrupted in neurodevelopmental disorders. Given that males are at least three times more likely to have autism than females, our work will also assess how these microglial processes differ depending upon sex. In the course of this work, we will develop much-needed viral tools for studying microglia in the brain. Our overarching goal is to lay the foundation for the development of new pharmacological strategies for treating neurodevelopmental disorders by restoring healthy microglial function during postnatal brain development. In addition to the high-risk/high-reward nature of the proposal, this project is particularly well-suited for the NIH Director’s New Innovator Award based upon conceptual novelty, promise to achieve key technological advances, and potential to alleviate a major healthcare burden affecting the United States and the world.

Project Narrative: Most studies of neurodevelopmental disorders focus on genetic mutations underlying rare subsets of conditions, while the environmental factors that contribute to a large swath of these disorders remain poorly understood. To tackle the vast biomedical problem of neurodevelopmental dysfunction from an environmental perspective, we will apply a diverse suite of functional, structural, molecular, and genomic methods to define the mechanisms through which impairments in communication between the immune system and the brain contribute to the circuit wiring deficits underlying neurodevelopmental disorders. By facilitating the design of new therapeutic strategies targeting neuro-immune signaling during a phase of heightened plasticity in the developing brain, we aim to curb the increasing prevalence of neurodevelopmental disorders in the American population and alleviate the suffering of millions world-wide.