Cholinergic Transmission in an Inducible Transgenic Mouse Model of Paroxysmal Dystonia

Abstract

Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in dystonia pathophysiology. Indeed, previous research across various genetic mouse models of human isolated dystonia has identified as a shared endophenotype with paradoxical excitation of striatal cholinergic interneurons (ChIs) activity in response to activation of dopamine D2 receptor (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of ACh transmission in the manifestation of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesigenic dyskinesia (PNKD). We found that, similarly to other genetic models, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing the striatal cholinergic network. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced cholinergic network synchronization. Together these observations suggest that D2Rs may play an important role in synchronizing the ChI network during heightened movement states. The "paradoxical excitation" described in dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and allows for phenotypic dystonia when lost.