# Cell Type Specific Genetic Manipulation to Dissect Cholinergic Interneuron Function and Plasticity in a Symptomatic Model of DYT1 Dystonia

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $502,161

## Abstract

Project Summary/Abstract
Cholinergic neurons (ChIs) are a central but poorly understood element of striatal circuitry. A considerable
literature strongly implicates ChI dysfunction in the pathogenesis of abnormal movements, especially in dystonia
and levodopa-induced dyskinesias in Parkinson disease. A common theme of these studies is that maladaptive
plastic changes cause aberrant ChI output and connectivity, promoting motor dysfunction. The central goal of
this proposal is to advance understanding of the cellular and synaptic mechanisms through which ChIs cause
motor dysfunction by employing novel selective genetic and chemical strategies in a recently validated model of
DYT1 dystonia.
Conditional Knock Out of torsinA from all striatal neurons (using Dlx5/6-Cre; “Dlx-CKO”) causes selective
neurodegeneration of dorsolateral striatal ChI. ChI degeneration occurs roughly coincident with the juvenile onset
of abnormal twisting movements in these mice, and selective ChI abnormalities are also present in postmortem
tissue from DYT1 subjects. These movements are suppressed by the same anti-muscarinic compounds used to
treat patients with DYT1 dystonia, establishing model therapeutic validity and suggesting shared
pathophysiology with human dystonia. Surviving striatal ChIs are enlarged and hyperexcitable, and receive
aberrant synaptic inputs. Selective ablation of these surviving ChI suppresses abnormal twisting, implicating
these cells as key contributors to abnormal movements. Based on these data, we hypothesize that
maladaptations in surviving ChIs drive motor dysfunction.
Successful completion of the proposed studies will fundamentally advance understanding of maladaptive
mechanisms whereby ChI function and connectivity drive abnormal movements, information highly significant
for multiple striatal diseases. We will first address our hypothesis by testing the necessity of striatal ChI
dysfunction in abnormal movement generation by selectively restoring torsinA to these cells (Aim 1), decisively
moving beyond the current association between these factors. We will determine if cholinergic dysfunction arises
primarily from intrinsic ChI abnormalities or defects in how they respond to afferents (Aim 2), and, informed by
Aims 1 and 2, will pursue translational studies (Aim 3) testing whether directly modulating the activity of surviving
ChIs can suppress dystonic-like movements. This proposal is therefore highly signifiant because it will define a
circuit-based model of motor dysfunction that will inform the design of targeted therapeutics.

## Key facts

- **NIH application ID:** 10336494
- **Project number:** 5R01NS110853-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** WILLIAM T. DAUER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,161
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336494

## Citation

> US National Institutes of Health, RePORTER application 10336494, Cell Type Specific Genetic Manipulation to Dissect Cholinergic Interneuron Function and Plasticity in a Symptomatic Model of DYT1 Dystonia (5R01NS110853-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10336494. Licensed CC0.

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