# Developmental cerebellar deficits caused by Chd8 haploinsufficiency

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $231,498

## Abstract

SUMMARY
The role of the cerebellum (CB) in proprioception and fine motor control is well-established, however more
recent studies also strongly implicate this structure in higher order cognitive functions such as language,
cognitive processing and affective regulation. Despite the tight relationship between these cerebellar functions
and Neurodevelopmental Disorders (NDDs) such as Autism Spectrum Disorder (ASD) and Intellectual
Disability (ID), the role of non-motor contributions of the CB is often overlooked in NDD research and
especially understudied in animal models of these disorders compared to structures such as the cerebral
cortex and hippocampus. With the emerging understanding that the CB plays a critical role in higher order
brain function and that perturbed cerebellar functioning can lead to ASD and NDD relevant phenotypes, there
is strong justification for focus on CB dysfunction in NDD animal models. De novo mutations in the chromatin-
remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic
causal factor strongly associated with ASD and more generally with NDDs. Individuals harboring de novo
heterozygous mutations in CHD8 typically present with hallmarks of ASD, cognitive disability, and
macrocephaly, with other phenotypes also present in some patients. Multiple mouse Chd8 models have been
published (including by our group), with heterozygous mutants exhibiting relevant phenotypes including
macrocephaly and behavioral deficits. To date, animal models of pathology associated with CHD8 mutation
have focused on the forebrain, and in particular the cerebral cortex. In published and preliminary studies, we
identified altered structure of the deep cerebellar nuclei and evidence of altered cerebellar anatomy and
physiology in mice harboring heterozygous Chd8 mutation. We hypothesize that cerebellar impact of Chd8
mutation contributes to higher order cognitive and behavioral pathology. Here, we propose initial work
towards testing this model, defining the impact of Chd8 haploinsufficiency on cerebellar structure and
function across anatomical, genomic, and electrophysiological dimensions. In Aim 1, we will test CB
sensitivity to Chd8 haploinsufficiency with regard to patterning and cell identity. In Aim 2, we will test for
phenotypes at the electrophysiological, transcriptomic and morphologic level in cerebellar neurons. These
experiments will establish impacts of heterozygous Chd8 mutation on the mouse CB, linking neuroanatomy,
neuronal function, and signaling. These studies will provide critical evidence for future work defining specific
phenotypes associated with heterozygous Chd8 ablation in the CB and towards building a circuit level
understanding of how Chd8 mutations impact connectivity within the CB and between the CB and other
structures. If successful, this work will lead to new avenues of research on cerebellar dysfunction in NDDs and
ASD by linking a high confidence and top priority gene...

## Key facts

- **NIH application ID:** 10491162
- **Project number:** 5R21MH126413-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Diasynou Fioravante
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,498
- **Award type:** 5
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491162

## Citation

> US National Institutes of Health, RePORTER application 10491162, Developmental cerebellar deficits caused by Chd8 haploinsufficiency (5R21MH126413-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10491162. Licensed CC0.

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