# Striatal Cholinergic Interneuron Dysfunction in Dystonia Pathophysiology

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $20,620

## Abstract

PROJECT SUMMARY
DYT1 dystonia is the most common inherited form of dystonia, a common and disabling neurological movement
disorder. Striatal dysfunction is thought to play a key role in dystonia pathophysiology, but it is unclear which
neuronal classes are dysfunctional and drive abnormal movement. Morphologic and electrophysiologic
abnormalities of striatal cholinergic interneurons (ChIs) have been observed in DYT1 mouse models, but many
of these models do not exhibit motor dysfunction. This barrier to dystonia research was overcome when the
Dauer lab generated an overtly symptomatic mouse model by conditionally knocking out torsinA from forebrain
cholinergic and GABAergic neurons (including all striatal neurons) using Dlx5/6-Cre (“Dlx-CKO”). These mice
exhibit dystonic-like twisting movements, selective degeneration of dorsal striatal ChIs, and morphologic and
electrophysiologic changes in surviving ChIs. Clinically effective anti-muscarinic drugs suppress twisting
movements in Dlx-CKO mice, establishing predictive validity and suggesting that aberrant function of remaining
(non-degenerating) ChIs contributes to abnormal movement. To explore this possibility, I performed
immunohistochemistry to determine intensity of phosphorylated ribosomal protein S6 (p-rpS6), a marker
correlated with ChI activity. My preliminary data demonstrate that torsinA null ChIs exhibit elevated
phosphorylated ribosomal protein S6 (p-rpS6), a finding consistent with altered ChI activity. Consistent with the
hypothesis that abnormal activity of these cells contributes to dystonic-like movements, the p-rpS6 increase is
selective to dorsal striatal (motor) ChIs and present only at behaviorally symptomatic ages. To examine whether
abnormal ChI signaling is necessary for abnormal movement, I selectively lesioned these cells from the striatum
of Dlx-CKO mice at symptomatic and pre-symptomatic ages and found that ChI ablation reverses and prevents
abnormal twisting movements in Dlx-CKO mice, establishing their central role in dystonic-like symptoms.
Based on my preliminary data and considerable published electrophysiological work implicating ChIs in dystonia
pathophysiology, I hypothesize that ChIs are functionally abnormal in Dlx-CKO mice, and modulating ChI
function is an effective therapeutic strategy. I will test this hypothesis with two aims: (1) defining the relationship
between ChI activity and dystonic-like limb clasping using Designer Receptor Exclusively Activated by Designer
Drugs (DREADD) technology and (2) determining if ChI-targeted genetic rescue of torsinA expression rescues
neuropathologic and behavioral phenotypes in Dlx-CKO mice. The proposed studies will rigorously assess ChI
dysfunction and therapeutic potential in one of the only overtly symptomatic rodent models of dystonia.
Completion of the proposed work will further my writing, technical, and scientific skills and facilitate my
development as a physician-scientist focused on neurologic disease.

## Key facts

- **NIH application ID:** 10065199
- **Project number:** 1F31NS113433-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jay Li
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $20,620
- **Award type:** 1
- **Project period:** 2020-08-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065199

## Citation

> US National Institutes of Health, RePORTER application 10065199, Striatal Cholinergic Interneuron Dysfunction in Dystonia Pathophysiology (1F31NS113433-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065199. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*