Striatal cholinergic transmission in an inducible transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia
Year: 2024
Type: article
Abstract: Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations 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-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, 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 ACh release in PNKD mice. 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 synchronization of ACh release. These observations suggest that the “paradoxical excitation” of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements. Graphical Abstract . In the striatum, the cells that produce ACh, the cholinergic interneurons (ChIs), can synchronize their spontaneous firing activity resulting in oscillatory ACh release in the delta frequency. This delta rhythmic activity has been linked to the coordination of movement. To investigate the role of striatal ACh rhythm in movement disorders, we tested whether striatal ACh oscillations are altered in a mouse model of a human movement disorder (PNKD), in which movement abnormalities are triggered by caffeine. (Top right) In normal mice (wild-type, WT), caffeine's stimulatory effect on locomotion is linked to increased ACh delta power (more synchrony among ChIs) and to the excitatory effects of the dopamine D2 receptors (D2Rs) activation on ChI activity. This behavioral, cellular and network profile is mirrored by pre-symptomatic PNKD mice before caffeine treatment (Bottom left). Upon exposure to caffeine, PNKD mice (like humans carrying the same gene mutation) develop a motor phenotype with dyskinesia and dystonia features, which is associated with reduced ACh delta oscillations and loss of the D2Rs excitatory effects on ChIs activity (Bottom right). These findings emphasize the pivotal role of ACh dynamics in motor control and highlight the connection between excitatory dopamine D2R effects on ChI activity and enhanced ACh delta oscillations, suggesting an essential role for excitatory D2R signaling in coordinating ChI firing for the generation of ACh delta oscillations crucial for proper movement sequencing. • In PNKD mice caffeine induces dystonic and dyskinetic involuntary movements. • Pre-symptomatic PNKD show enhanced ACh delta oscillations; D2Rs increase ChI firing. • Abnormal movements in PNKD mice are accompanied by disrupted ACh delta oscillations. • Dystonia-inducing caffeine reverses excitatory D2R effects on ChI firing rate. • D2Rs may participate in synchronizing ChIs to produce ACh delta oscillations.
Source: Neurobiology of Disease
Institutions: University of Alabama at Birmingham, UAB Medicine
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
OpenAlex ID: W4402905397