# Molecular and Cellular Mechanisms of Cerebellar Dysfunction in Neurodevelopmental disorders

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $632,243

## Abstract

PROJECT SUMMARY
Neurodevelopmental disorders (NDDs) encompass a broad constellation of highly prevalent and etiologically
heterogeneous disorders that share several key diagnostic features. These include motor incoordination,
abnormal sensory processing, intellectual and developmental disabilities, epilepsy, and neuropsychiatric co-
morbidities such as autism, anxiety, and attention deficit and hyperactivity disorder (ADHD). Together, these
findings suggest that NDDs result from the perturbations of brain regions critical for motor, non-motor, and
sensorimotor information processing. One such region is the cerebellum, which forms multiple circuits with
cortical and subcortical regions to modulate movement, language, cognition, sensory processing, executive
function, and social behaviors. Intriguingly, cerebellar vermian hypoplasia (CVH) is a common neuroanatomical
finding in NDDs and lesions or malformations of the vermis result in communication and behavioral deficits,
suggesting that disrupted cerebellar development may perturb multi-modal information processing. In 2016, we
and others discovered that a previously unrecognized NDD, the Hypotonia, Ataxia, and Delayed Development
syndrome (HADDS, MIM#617330), results from either heterozygous loss-of-function (LOF) or single gene
deletions of Early B-Cell Factor 3 (EBF3). EBF3-related NDDs are characterized by the namesake features,
co-morbid autism, atypical cerebellar foliation, and CVH. EBF3 encodes a Collier/Olf/EBF3 (COE) transcription
factor that regulates multiple neurodevelopmental processes, including GABAergic-inhibitory neuronal
differentiation. We found that Ebf3 haploinsufficiency in mice recapitulated analogous neurobehavioral deficits
and cerebellar dysmorphisms. Hence, elucidating the molecular and cellular mechanisms of EBF3-related
NDDs affords a unique opportunity to study the impact of cerebellar dysfunction in NDDs. The primary goal of
this proposal is to understand the molecular and cellular mechanisms of cerebellar inhibitory neuronal
dysfunction in NDD pathogenesis through a detailed dissection of a well-defined monogenic disorder. Our
unifying central hypothesis is that cerebellar inhibitory Purkinje cells and GABAergic interneurons are
vulnerable to EBF3 LOF and lead to cerebellar dysfunction in EBF3-related NDDs. We will define the spectrum
of cerebellar deficits, molecular alterations, and phenotype-genotype correlations in EBF3-related NDDs (Aim
1), identify Ebf3 expression in the cerebellum and associated gene regulatory networks for cerebellar inhibitory
neuronal development (Aim 2), and determine the vulnerability of cerebellar inhibitory and excitatory neurons
to Ebf3 LOF (Aim 3). This proposal focuses on incorporating in-depth human phenotyping with integrated
mechanistic studies of Ebf3 haploinsufficiency at the cell-type-specific level in mouse models. The cross-
species approaches in this project provide innovative opportunities to elucidate the interplay betwe...

## Key facts

- **NIH application ID:** 10981992
- **Project number:** 1R01NS134596-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** HSIAO-TUAN CHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,243
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981992

## Citation

> US National Institutes of Health, RePORTER application 10981992, Molecular and Cellular Mechanisms of Cerebellar Dysfunction in Neurodevelopmental disorders (1R01NS134596-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981992. Licensed CC0.

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