Summary
A bioRxiv preprint in a DYT-TOR1A mouse model links striatal cholinergic interneuron pathology to abnormal movements while showing that antimuscarinic drugs can act without those neurons being present. The findings separate a developmental role for the neurons from the circuit mechanism through which the drugs suppress movements.
A study in mice has separated two processes involved in DYT-TOR1A dystonia: damage to a population of striatal neurons during development, and the muscarinic signalling through which antimuscarinic drugs reduce abnormal movements. The findings, reported as a bioRxiv preprint by researchers at UT Southwestern and the University of Michigan, identify cholinergic interneuron pathology as a contributor to motor dysfunction but show that the continued presence of these neurons is not required for either the movement disorder or its suppression by the drugs.
A developmental role for striatal cholinergic interneurons
DYT-TOR1A is a genetic form of dystonia, a movement disorder involving involuntary muscle contractions and abnormal postures. The striatum, a movement-related region of the brain, contains cholinergic interneurons that release acetylcholine and help regulate local neural circuits. Drugs that block muscarinic receptors, which respond to acetylcholine, are among the most effective pharmacological treatments for dystonia, although the relevant cellular mechanisms have been difficult to identify.
The researchers used a symptomatic mouse model in which torsinA, the protein affected in DYT-TOR1A, was lost from all striatal neurons. In these mice, cholinergic interneurons selectively degenerated during juvenile maturation. The surviving neurons also showed persistent changes in their shape, electrical activity and connections.
The study found that surviving cholinergic interneurons became unusually active at the same time that degeneration and abnormal movements emerged. In a complementary genetic experiment, restoring torsinA selectively in these neurons before birth prevented their degeneration and reduced abnormal movements. Together, these results identify cholinergic interneuron pathology as an important cellular site through which torsinA loss contributes to motor dysfunction in the model.
Drug action did not require the remaining neurons
The experiments produced a separate result for antimuscarinic treatment. Giving an antimuscarinic drug throughout juvenile striatal maturation produced behavioural improvement that continued after treatment ended, but it did not prevent cholinergic interneuron degeneration. This separates the drug’s lasting behavioural effect from preservation of those neurons.
The location of drug action was tested directly. Delivering an antimuscarinic drug into the striatum nearly abolished abnormal movements, identifying the striatum as a critical site for the treatment effect.
The researchers then extensively removed the remaining cholinergic interneurons in the dorsal striatum. Their removal neither prevented nor improved abnormal movements. It also did not reduce the effectiveness of systemic or directly striatal antimuscarinic treatment. The result indicates that cholinergic interneuron pathology can help establish the motor phenotype, while the surviving dorsal striatal cholinergic interneurons are not necessary for the phenotype to be expressed or for muscarinic antagonists to suppress it.
This distinction points to muscarinic signalling elsewhere in the striatal circuit as an important part of the drug response. The preprint does not identify the precise downstream cells or circuit elements responsible. Its evidence is also limited to a symptomatic mouse model and is presented before peer review, so the findings provide a mechanistic framework for further dystonia research rather than a demonstrated change to human treatment.