Objective: Define the differences in electrophysiological signatures of cerebellar output between mouse models of dystonia with diverse severity and manifestation.

Background: Dystonia is heterogeneous movement disorder, with a wide range of manifestations of symptoms between patients, even between carriers of the same disease-causing mutations. Aberrant signaling in the cerebellar nuclei, comprised of the cerebellar output neurons, has been found in mouse models of dystonia, and neuromodulation targeted to cerebellar nuclei alleviates symptoms in mice and human patients. Here, we test the hypothesis that the cerebellar nuclei function as a fulcrum in the manifestation of dystonia-associated motor impairments.

Method: We performed single-unit recordings mouse models of dystonia with different manifestations and symptom severity. These models include a genetic model for DYT6 (Thap1^+/-) that have a mild tremor but no other dystonia-like symptoms [1], a genetic model for dystonia with severe tremor and dystonia-like muscle contractions (Ptf1a^Cre/+;Vglut2^fl/fl+­) that are alleviated with deep brain stimulation targeted to the cerebellar nuclei [2], and a pharmacological model for DYT12 (cerebellar ouabain infusion) with severe dystonia-like symptoms. We used principal component analysis, unbiased cluster analysis, and an unsupervised classification learner to define which aspects of the cerebellar firing patterns are most distinct between mouse models of different dystonia severities.

Results: The electrophysiological signature of cerebellar output neurons is distinct between mouse models of dystonia with different disease manifestations and severity. We found that cerebellar output neurons in mice with the most severe symptoms had electrophysiological properties most distinct from control mice. Specifically, a reduced firing frequency best predicted the presence of tremor in mice, whereas irregular firing patterns best predicted the presence of dystonia-like muscle contractions in mice.

Conclusion: The presence of irregular firing patterns may drive the manifestation of dystonia-like muscle contractions. Pharmacological or neuromodulatory approaches that decrease the irregularity of electric signals from cerebellar output neurons may best reduce the severity of dystonia-like symptoms in patients.

References: [1] van der Heijden ME, Kizek DJ, Perez R, Ruff EK, Ehrlich ME, Sillitoe RV. Abnormal cerebellar function and tremor in a mouse model for non-manifesting partially penetrant dystonia type 6. J Physiol. 2020 Dec 28. doi: 10.1113/JP280978. Epub ahead of print. PMID: 33369735. [2] White JJ, Sillitoe RV. Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat Commun. 2017 Apr 4;8:14912. doi: 10.1038/ncomms14912. PMID: 28374839; PMCID: PMC5382291.

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