# Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $531,012

## Abstract

Project Summary
No targeted therapies exist for treatment of Autism Spectrum Disorders (ASD), as the underlying mechanisms
remain poorly understood. Recent studies implicate the cerebellum in the pathogenesis of ASD, and we have
recently shown that cerebellar dysfunction is sufficient to generate ASD-relevant behaviors. However, the
contribution of cerebellar dysfunction to these behaviors in Fragile X Syndrome (FXS) is unknown.
FXS is the most significant monogenic cause of ASD, and cerebellar dysfunction has been implicated in the
pathogenesis of both ASD and FXS. Previous studies have demonstrated important roles for Fmr1 in the
cerebellum – from dendritic morphology to synaptic plasticity; however, the contribution of cerebellar
dysfunction to autism-relevant behaviors in FXS remains unknown. In this proposal, we hypothesize and
present preliminary data to support that cerebellar Fmr1 dysfunction is sufficient to generate ASD behaviors,
including social dysfunction and sensory hypersensitivity. To evaluate this hypothesis, we propose in Aim1 to
establish the role for Purkinje cell Fmr1 in the regulation of ASD-relevant behaviors and to further evaluate
electrophysiological and molecular mechanisms that are disrupted upon loss of cerebellar Fmr1.
With evidence that cerebellar dysfunction contributes to ASD behaviors, we also hypothesized and have
generated preliminary data to support specific cerebellar lobule CrusI involvement in ASD-related behaviors
and circuit connections between this lobule and the parietal association cortex, a region implicated in ASD and
in sensory processing. In Aim2, we will delineate the involvement of right CrusI – parietal association cortex
circuits in ASD-relevant behaviors and investigate the impact of circuit modulation on ASD-relevant behaviors
and cortical hyper-excitability in the cerebellar FXS mouse model.
Lastly, we also hypothesize and show preliminary data to support that normalization of cerebellar function
might itself be sufficient to ameliorate ASD-related behaviors in a global (whole body knockout) model of FXS.
In Aim3, we will delineate the benefit of reintroduction of Fmr1 specifically into the cerebellum in an otherwise
global Fmr1 mutant mouse. In addition, we will further evaluate the potential benefit of cerebellar
neuromodulation in this global Fmr1 mutant mouse model on behavior and cortical hyper-excitability.
Taken together, in this proposal, we will establish the roles for Fmr1 in the cerebellum and establish its
contribution to autism-related behaviors. We will additionally examine the molecular mechanisms driving these
contributions and examine the benefits of reintroduction of Fmr1 within the cerebellum in an otherwise global
Fmr1 mutant. Lastly, we will examine the benefit of cerebellar neuromodulation on ASD-relevant behaviors in
cerebellar and global FXS mouse models. Thus, these studies will not only further our understanding of basic
molecular and circuit mechanisms of ASD-rele...

## Key facts

- **NIH application ID:** 10834732
- **Project number:** 5R01MH120069-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Peter T. Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $531,012
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834732

## Citation

> US National Institutes of Health, RePORTER application 10834732, Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome (5R01MH120069-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10834732. Licensed CC0.

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