# Spatial and temporal pathophysiology of developmental dystonia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $389,213

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurological and neuropsychiatric diseases are a growing concern worldwide, as the consequences
are often lethal, or at best they leave patients incapacitated. One such disease is dystonia, which
overwhelms affected people with severe motor difficulties including painful muscle over-contractions,
twisting of the body and tremor in the limbs. Despite recent efforts in identifying the brain circuits that
contribute to dystonia, as well as the success of deep brain stimulation (DBS) as a therapy for adults,
pediatric patients face unique long-term health concerns, with poor treatment options for many kids
since the timing of disease onset is unclear. Such barriers arise as developing circuits are dynamic;
and functional changes that promote brain maturation create hurdles for using deep brain stimulation.
An overarching problem, however, is that we currently have little insight into how the brain regions
and circuits that mediate dystonia emerge during embryonic and early postnatal life. As a first step
towards better defining the developmental mechanisms that instigate dystonia, we have found that
conditional loss of a single gene, engrailed1 (En1), which is required for brain morphogenesis, results
in severe dystonia in mice. En1 and its homolog engrailed 2 (En2) are homeobox-containing genes
that cooperate to control midbrain and hindbrain development. The basal ganglia, which are partly
located in the midbrain, and the cerebellum, which is entirely located within the hindbrain, are the two
main structures that are thought to drive dystonia pathophysiology. Intriguingly, manipulations of En1
alone leave the basal ganglia intact, but alter cerebellar circuit patterning. Based on the cerebellar
focus of the En1 conditional phenotype, we argue that severe dystonia originates from genetically-
defined defects that disrupt cerebellar circuit maturation. We generated three specific aims to test this
hypothesis in vivo. In Aim1, we will use conditional genetic manipulations in combination with in vivo
electrophysiology and quantitative behavioral paradigms to uncover the temporal dependence of En1
in setting the severity of developmental dystonia. In Aim2, we will perform cell-type specific deletions
of En1 and then conduct in vivo electrophysiology in behaving pups to define the neural signatures of
the En1-dependent cerebellar circuits that trigger early-onset dystonia. Although the cerebellum and
basal ganglia are present in En1 mutants, it is unclear if their circuits are mis-wired to a point that is
beyond repair. In Aim3, we will use the En1 lineage to target optogenetic DBS to the cerebellum and
basal ganglia to test which region restores mobility in En1 mutants. Then, we will deliver optogenetic
stimulation to the En1 lineage in control mice to test which of these regions can initiate dystonia in
otherwise normal young and adult mice. Designing better treatment options for incurable motor
diseases will improve healthcare...

## Key facts

- **NIH application ID:** 10812437
- **Project number:** 5R01NS127435-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Roy Vincent Sillitoe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,213
- **Award type:** 5
- **Project period:** 2022-04-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812437

## Citation

> US National Institutes of Health, RePORTER application 10812437, Spatial and temporal pathophysiology of developmental dystonia (5R01NS127435-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10812437. Licensed CC0.

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