# Functional Genomic Interrogation of Autism Spectrum Disorder Genetic Risk on Microglia-Neuronal Interactions

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $41,308

## Abstract

PROJECT SUMMARY/ABSTRACT
Autism spectrum disorder (ASD) is a lifelong, common neurodevelopmental disorder (NDD) with high heritability
and complex genetic architecture. Known genetic risk factors, including large effect, de novo mutations that
cause approximately 10% of ASD cases, have their maximal expression and converge during early brain
development to impact neurogenesis and neuronal development. Yet, multiple analyses of post-mortem brain
from individuals with ASD have consistently identified pervasive microglial activation. Study of cortical
development in ASD has centered around neurons. So, there is a dearth of knowledge surrounding microglia
function in the developing brain in ASD, which is especially important because microglia colonize the developing
fetal cortex during the epoch during in which ASD risk genes converge. Here, I propose to leverage advances in
human stem cell (SC) culture, including the development and validation of 3D human cortical spheroid (hCS)
models of human brain development, to assess the impact of ASD genetic risk and neuronal-microglial
interactions on microglial function. Cell lines derived from control, non-ASD, SC lines and two SC lines with a
haploinsufficiency of high-risk ASD-associated genes (CHD8 and SCN2A) will be utilized to derive microglia and
hCS. Bulk transcriptomics, morphological analysis, and phagocytosis assays of microglia from SC lines
harboring high risk ASD-associated mutations will reveal how ASD genetic risk impacts microglia physiology,
independent of interactions with neuronal cell types (Aim 1). Transcriptomes will be mapped to the in vivo
developmental trajectory of microglia, and differential gene expression analysis will be performed on the ASD
microglia relative to controls. Perturbations to cortical neurogenesis in ASD will be assessed through single cell
RNA sequencing and immunohistochemical analysis of cell type and morphology in a 3D co-culture system of
human cortical spheroids (hCS) integrated with microglia to model fetal microglial colonization of the cortex (Aim
2). Cell type distribution, differential gene expression, and gene network analysis of ASD mutant hCS compared
to controls at early and late neurogenesis will be performed; immunohistochemistry of cell populations, synapses,
and microglial morphology will validate and extend transcriptomic findings. These experiments will help inform
ASD pathophysiology by elucidating how ASD genetic risk contributes to microglial activation and neuronal-
microglial signaling and provide a framework for testing other ASD risk mutations. This training plan will prepare
this applicant for a successful career as a physician-scientist studying neurodevelopmental disorders (NDDs),
via the following major goals: training in stem cell culture and functional genomics, rigor and ethics in scientific
thinking, professional development, and translation of research into the clinical setting. Working in a
collaborative, multidisciplinary la...

## Key facts

- **NIH application ID:** 10999203
- **Project number:** 1F30MH135660-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Natalie Hawken
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,308
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999203

## Citation

> US National Institutes of Health, RePORTER application 10999203, Functional Genomic Interrogation of Autism Spectrum Disorder Genetic Risk on Microglia-Neuronal Interactions (1F30MH135660-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10999203. Licensed CC0.

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