Striatal cholinergic interneuron pathology and muscarinic signaling independently shape motor dysfunction in a DYT-TOR1A dystonia model

Antimuscarinic drugs are among the most effective pharmacological treatments for dystonia, yet the neural substrates underlying their therapeutic effects remain poorly understood. Striatal cholinergic interneurons (ChI) are strongly implicated in dystonia pathophysiology. In a symptomatic mouse model of DYT-TOR1A dystonia, torsinA loss from all striatal neurons causes selective ChI degeneration during juvenile maturation; surviving ChI exhibit persistent morphological, physiological, and connectivity abnormalities. Whether motor dysfunction arises from ChI degeneration, dysfunction of surviving ChI, or altered cholinergic signaling elsewhere in the striatal circuit remains unknown. Here, we distinguish these mechanisms using complementary genetic, pharmacological, and cell-ablation approaches. Surviving ChI became hyperactive coincident with the emergence of neurodegeneration and abnormal movements. Selective prenatal restoration of torsinA in ChI prevented their degeneration and reduced abnormal movements, identifying ChI as an important cellular locus of torsinA-dependent motor dysfunction. Systemic antimuscarinic treatment during juvenile striatal maturation produced persistent behavioral improvement outlasting treatment without preventing ChI degeneration. Direct intrastriatal antimuscarinic administration nearly abolished abnormal movements, identifying the striatum as a critical site of therapeutic action. Surprisingly, extensive ablation of the remaining dorsal striatal ChI neither prevented nor ameliorated abnormal movements and did not diminish the efficacy of systemic or intrastriatal antimuscarinic treatment. Thus, torsinA-dependent ChI pathology contributes causally to motor dysfunction, yet the continued presence of dorsal striatal ChI is not required for either expression of the motor phenotype or its suppression by muscarinic antagonists. These findings dissociate a developmental contribution of ChI pathology from the striatal mechanisms through which antimuscarinic drugs suppress dystonia-related movements.

Leedy, C. E., Li, J., Pappas, S. S., Dauer, W. T.

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