# Striatal cell-type specific molecular adaptations in a mouse model of dystonia

> **NIH NIH R21** · EMORY UNIVERSITY · 2020 · $416,112

## Abstract

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and
postures. Striatal dysfunction has been implicated in many forms of dystonia, including idiopathic dystonias,
inherited dystonias and iatrogenic dystonias. The vast majority of neurons in the striatum are GABAergic spiny
projection neurons (SPNs). SPNs express either D1 dopamine receptors (D1Rs) or D2 dopamine receptors
(D2Rs). D1Rs are expressed on direct pathway SPNs (dSPNs) that project to the GPi to promote movement.
D2Rs are expressed on indirect pathway SPNs (iSPNs) that project to the external pallidum (GPe) to inhibit
movement. Convergent results from genetic, imaging and physiological studies in patients suggest that
abnormalities of both dSPNs and iSPNs contribute to the expression of dystonia. Despite the overwhelming
evidence implicating striatal dysfunction in dystonia, the precise nature of the striatal defects that give rise to
dystonia are not known.
Research focused on understanding striatal dysfunction in dystonia has been stymied by the lack of animal
models with dystonic movements that are specifically associated with striatal dysfunction. To overcome this
obstacle, we recently generated a knockin mouse model of DOPA-responsive dystonia (DRD). The DRD mouse
strain carries the human DRD-causing Q381K mutation in tyrosine hydroxylase (ThDRD; DRD mice). Like the
human disorder, DRD mice exhibit dystonic movements that that improve in response to L-DOPA administration.
Notably, striatal DA neurotransmission, including abnormal D1R and D2R signaling, plays a central role in the
expression of dystonia. Thus, this novel mouse model provides an unparalleled opportunity to understand the
molecular mechanisms underlying dSPN and iSPN dysfunction in dystonia.
The Specific Aim is to identify cell-type specific changes in the translatome of dSPNs and iSPNs in DRD mice.
In light of how little is known about striatal dysfunction in dystonia, a hypothesis-generating approach that
provides a comprehensive account of dSPN and iSPN cell-type specific molecular adaptations is needed to fully
decipher the pathogenesis of dystonia. However, a major challenge to understanding cell-type specific molecular
changes in dystonia is the complexity of striatal anatomy. Because dSPNs and iSPNs are intermingled
throughout the striatum, traditional whole tissue RNA-seq is not useful for delineating cell-type specific
abnormalities. Therefore, we will isolate translating ribosomes (Translating Ribosome Affinity Purification
(TRAP)) from genetically identified dSPNs and iSPNs in normal and DRD mice to identify abnormally regulated
processes and pathways associated with dystonia. This approach will provide unprecedented insight into the
cell-type specific molecular abnormalities in dystonia.

## Key facts

- **NIH application ID:** 10057917
- **Project number:** 1R21NS114882-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ELLEN J. HESS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,112
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057917

## Citation

> US National Institutes of Health, RePORTER application 10057917, Striatal cell-type specific molecular adaptations in a mouse model of dystonia (1R21NS114882-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10057917. Licensed CC0.

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