Jul 9, 2026 | 16.30 | Zoom
Meike van der Heijden
All models are wrong, some are useful – Lessons learned from a preclinical dystonia model.
Dystonia is a complex movement disorder characterized by abnormal muscle contractions, heterogeneous clinical presentations, incomplete genetic penetrance, and dysfunction across multiple brain regions. These features have made it challenging to identify disease mechanisms and develop effective therapies. In this talk, I describe how a highly tractable cerebellar mouse model of dystonia has provided new insights into the neural and developmental mechanisms underlying dystonia.
Using this model, we examined how cerebellar dysfunction shapes motor and vocal behaviors across development. Our studies demonstrate that cerebellar nuclei activity patterns associated with dystonia are distinct from those observed in ataxia and tremor, suggesting that specific patterns of neural dysfunction contribute to the emergence of different movement disorders. We also found that Purkinje cell activity limited predictive power for cerebellar nuclei activity, challenging common assumptions regarding cerebellar Purkinje cell as biomarkers and therapeutic targets. Longitudinal analyses revealed substantial variability in symptom severity both within and between genetically identical animals, indicating that dystonia arises through dynamic developmental processes rather than genotype alone. Finally, we show that cerebellar circuit dysfunction alters vocal behavior in ways that parallel features of human laryngeal dystonia, highlighting a potential role for the cerebellum in vocal motor control.
Together, these findings illustrate how preclinical models can provide mechanistic insight into the complexity of dystonia while revealing important limitations in traditional approaches to model validation. The results support a framework in which dystonia emerges from specific patterns of cerebellar circuit dysfunction that evolve during development and may ultimately inform the discovery of biomarkers and circuit-based therapeutic strategies.
