# Mapping the cellular impacts of Chd8 haploinsufficiency and characterizing microglial activity in Chd8 mutant mice

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,568

## Abstract

PROJECT SUMMARY
Autism spectrum disorder (ASD) is part of a larger group of neurodevelopmental disorders (NDDs) and is
diagnosed in more than 1% of the human population1-3. Patients with severe forms of ASD live with debilitating
symptoms that can prevent them from living independent lives. ASD has a strong genetic component, but is
genetically heterogenous1, 4-7. Whole exome studies have identified hundreds of risk loci, including the
Chromodomain Helicase DNA-binding protein 8 (CHD8) gene2, 8-12. CHD8 is a chromatin remodeling factor
(CRF)13-16 and has a high occurrence of de novo loss-of-function mutations in ASD cohorts8-11, 17-20. Moreover,
along with ASD, CHD8 mutation carriers frequently exhibit intellectual disability (ID), macrocephaly, and gut
dysfunction21-22. Our lab generated and characterized mice with germline heterozygous loss of function mutations
to Chd8, finding macrocephaly and disrupted cognitive function, as well as ASD relevant transcriptional
pathology during neurodevelopment23. While we and others have characterized Chd8 mutant mouse lines and
human in vitro models, the molecular underpinnings of core ASD pathology in Chd8 haploinsufficient mice are
still not well understood. CHD8 has been shown to bind regulatory targets in the genome in brain development
and adulthood, impacting neurodevelopmental gene expression programs. The primary hypothesis in the field is
that CHD8 haploinsufficiency drives ASD pathology by first disturbing neurogenesis and developmental
processes, but there may also be disturbances to synaptic function in adulthood that perpetuate and exacerbate
cognitive and behavioral symptoms23-24. In addition to core symptoms, 69% of ASD patients exhibit increased
neuroinflammation or microglial activation25. Studies on postmortem ASD brain samples indicated increased
expression of immune related genes27-28. The neuroimmune interface in Chd8 haploinsufficient mice has yet to
be characterized in significant detail, and the neuroimmune signatures seen in human ASD patients have not
previously been observed in mouse models. Intriguingly, our transcriptomic studies have revealed preliminary
evidence of perturbed immune pathways in the brain23. Whether these immune symptoms are an intrinsic part
of CHD8-mediated pathology or secondary to disruptions in other pathways is uncertain. In this proposal, I will
leverage Chd8 mutant mice to elucidate cell-specific transcriptomic mechanisms associated with Chd8
haploinsufficiency and NDD-associated pathology. My studies will secondly test for microglia-specific effects of
Chd8 mutation and map the relationship between immune and neuronal signatures in the brain. This work will
comprehensively expand the breadth of our understanding of molecular pathology across cell types in the adult
brain, as well as interrogate at depth the impacts of Chd8 haploinsufficiency on neuroimmune signaling and
microglia. Overall, these studies may provide novel insights into cellular and mole...

## Key facts

- **NIH application ID:** 10903003
- **Project number:** 1F31HD113328-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Stephanie Lozano
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,568
- **Award type:** 1
- **Project period:** 2024-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903003

## Citation

> US National Institutes of Health, RePORTER application 10903003, Mapping the cellular impacts of Chd8 haploinsufficiency and characterizing microglial activity in Chd8 mutant mice (1F31HD113328-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10903003. Licensed CC0.

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