Neuroimmunological insights into brain development and dysfunction: an integrative approach focused on microglial dynamics

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.

Grant Number: 4DP2MH132943-02
NIH Institute/Center: NIH
Principal Investigator: Lucas Cheadle