The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network.

Knorr S, Rauschenberger L, Pasos UR, Friedrich MU, Peach RL, Grundmann-Hauser K, Ott T, O'Leary A, Reif A, Tovote P, Volkmann J, Ip CW.
Neurobiol Dis.


TOR1A is the most common inherited form of dystonia with still unclear¬†pathophysiology¬†and reduced¬†penetrance¬†of 30‚Äď40%. ‚ąÜETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ‚ąÜETorA rats by¬†peripheral nerve injury¬†and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the¬†tail suspension test¬†and implementing a pipeline of deep learning applications. Neuron numbers of striatal¬†parvalbumin+, nNOS+,¬†calretinin+,¬†ChAT+¬†interneurons and Nissl+¬†cells were estimated by unbiased¬†stereology. Striatal¬†dopaminergic¬†metabolism was analyzed via in vivo¬†microdialysis, qPCR and¬†western blot.¬†Local field potentials¬†(LFP) were recorded from the central motor network.¬†Deep brain stimulation¬†(DBS) of the¬†entopeduncular nucleus¬†(EP) was performed. Nerve-injured ‚ąÜETorA rats developed long-lasting DLM over 12¬†weeks. No changes in striatal structure were observed. Dystonic-like ‚ąÜETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ‚ąÜETorA compared to wt rats was recorded. Chronic EP-DBS over 3¬†weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human¬†TOR1A¬†pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.

Published: Jul 2021