# Neural basis of locomotor dysfunction in Down Syndrome

> **NIH NIH R21** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $490,875

## Abstract

PROJECT SUMMARY
Down syndrome (DS) is the most commonly diagnosed chromosomal condition and the most common genetic
cause of intellectual disability in the US. DS affects a range of behavioral domains in children, including motor
and cognitive function. While atypical cognitive processing has been well studied in DS, locomotor dysfunction
is relatively understudied. Clinical assessments indicate a range of locomotor deficits in DS, as well as slower
adaptive control. Longitudinal data also indicates altered gait evolution from childhood to adulthood. Cerebellar
pathology has been consistently observed in DS, and is thought to contribute to dysfunction in locomotor and
adaptive motor skills. Studies in animal models of DS have also indicated deficient cerebellar processing.
However, the specific pathways underlying locomotor deficits and the cerebellar circuits that are disrupted in
DS remain poorly understood. Defining specific abnormalities in motor behavior, and identifying the brain
regions and neurons which are functionally involved will provide the basis for developing potential therapies for
treating motor problems in individuals with DS. The main goal of this proposal is to identify specific alterations
in the circuitry of the cerebellum that result in locomotor dysfunction in DS. Our preliminary data show
locomotor miscoordination, adaptive motor learning deficits, and cerebellar synaptic alterations in the Ts65Dn
mouse model of DS. To quantify locomotor behavior, we used the ErasmusLadder, an advanced tool capable
of measuring locomotor coordination and adaptive cerebellar learning. Our analysis in postnatal Ts65Dn mice
shows that Purkinje cells (PCs), which are the sole output of the cerebellar cortex, receive fewer excitatory
synapses from climbing fibers (CFs) than normal. This finding is significant, as cerebellar-dependent learning
depends on strong monosynaptic excitatory input from CFs onto PC dendrites. Based on our data, we
hypothesize that locomotor dysfunction and adaptive motor deficits in the Ts65Dn mouse model of DS are
caused by disruption of CF input to PCs. To test this hypothesis, in Aim 1 we will define changes in PC circuitry
that are linked to abnormal synaptic input to PCs and to locomotor learning deficits in Ts65Dn mice. We will
analyze locomotor dysfunction and identify molecular changes in cerebellar circuitry to define potential synaptic
alterations in the cerebellar cortex. In Aim 2, we will establish the precise correlation between
pathophysiological changes in PC activity and locomotor abnormalities in freely-behaving animals, and
determine whether enhancing excitatory input to PCs will restore locomotor function in Ts65Dn mice. We will
use an advanced technique established in our lab that employs GCaMP6f fiber photometry in order to time-
lock PC activity in the cerebellum to ErasmusLadder behavioral data. We will attempt at rescuing abnormalities
in PC activity and locomotor behavior in Ts65Dn mice by spec...

## Key facts

- **NIH application ID:** 10091905
- **Project number:** 1R21NS119344-01
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Vittorio Gallo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,875
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091905

## Citation

> US National Institutes of Health, RePORTER application 10091905, Neural basis of locomotor dysfunction in Down Syndrome (1R21NS119344-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10091905. Licensed CC0.

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