Peripheral nerve injury elicits microstructural and neurochemical changes in the striatum and substantia nigra of a DYT-TOR1A mouse model with dystonia-like movements.

Authors
Rauschenberger L, Krenig EM, Stengl A, Knorr S, Harder TH, Steeg F, Friedrich MU, Grundmann-Hauser K, Volkmann J, Ip CW.
Journal
Neurobiol Dis.

Abstract

The relationship between genotype and phenotype in DYT-TOR1A dystonia as well as the associated motor circuit alterations are still insufficiently understood. DYT-TOR1A dystonia has a remarkably reduced¬†penetrance¬†of 20‚Äď30%, which has led to the second-hit hypothesis emphasizing an important role of extragenetic factors in the symptomatogenesis of TOR1A mutation carriers. To analyze whether recovery from a¬†peripheral nerve injury¬†can trigger a dystonic phenotype in asymptomatic hőĒGAG3 mice, which overexpress human mutated torsinA, a¬†sciatic nerve¬†crush was applied. An observer-based scoring system as well as an unbiased deep-learning based characterization of the phenotype showed that recovery from a sciatic nerve crush leads to significantly more dystonia-like movements in hőĒGAG3 animals compared to wildtype control animals, which persisted over the entire monitored period of 12¬†weeks. In the¬†basal ganglia, the analysis of¬†medium spiny neurons¬†revealed a significantly reduced number of dendrites, dendrite length and number of spines in the na√Įve and nerve-crushed hőĒGAG3 mice compared to both wildtype control groups indicative of an endophenotypical trait. The volume of striatal¬†calretinin+¬†interneurons¬†showed alterations in hőĒGAG3 mice compared to the wt groups. Nerve-injury related changes were found for striatal¬†ChAT+,¬†parvalbumin+¬†and¬†nNOS+¬†interneurons in both genotypes. The¬†dopaminergic¬†neurons of the¬†substantia nigra¬†remained unchanged in number across all groups, however, the cell volume was significantly increased in nerve-crushed hőĒGAG3 mice compared to na√Įve hőĒGAG3 mice and wildtype littermates. Moreover, in vivo¬†microdialysis¬†showed an increase of dopamine and its metabolites in the striatum comparing nerve-crushed hőĒGAG3 mice to all other groups. The induction of a dystonia-like phenotype in genetically predisposed DYT-TOR1A mice highlights the importance of extragenetic factors in the symptomatogenesis of DYT-TOR1A dystonia. Our experimental approach allowed us to dissect microstructural and neurochemical abnormalities in the basal ganglia, which either reflected a¬†genetic predisposition¬†or¬†endophenotype¬†in DYT-TOR1A mice or a correlate of the induced dystonic phenotype. In particular, neurochemical and morphological changes of the nigrostriatal dopaminergic system were correlated with symptomatogenesis.

Published: Apr 2023
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