Dystonia genes and their biological pathways

Fonzo, Alessio Di; Jinnah, Hyder A.; Zech, Michael

doi:10.1016/bs.irn.2023.04.009

Cited by 2 publications

(9 citation statements)

References 154 publications

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“… A) ACh sensor expression in dorsolateral striatum, in vivo fiber photometry setup and analysis pipelines. B) Example GRAB-ACh fluorescence trace ([1] ΔF/F) in a WT and C) in a PNKD mouse during spontaneous movement ([2] instantaneous locomotion speed from animal tracking). D) Mean normalized power spectra of the ACh signal at baseline in WT (black, N=5) and PNKD mice (blue, N=6).…”

Section: Resultsmentioning

confidence: 99%

“…Points are mean + SEM. (Middle, [2]) Colormaps of the average frequency spectra obtained by Morlet Wavelet convolution of the ΔF/F photometry signals. Average over time of the power spectrum shows changes of the delta power at different time windows after caffeine injection ( WT : 1-way ANOVA, treatment: F (2,192) = 9.2, p=0.0002; ns baseline vs 10min; **** baseline vs 30min, Dunnett’s multiple comparisons test.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, the ACh delta power did not change over time after vehicle injections (Figure 4F and Suppl. Figure 1B [2]). In PNKD mice, caffeine increased the speed of locomotion in the first 10 min post-injection prior to the onset of a measurable dystonic phenotype ( Figure 4D [3]), which was again associated with enhanced ACh delta power ( Figure 4B-D [2]).…”

Section: Resultsmentioning

confidence: 99%

“…Figure 1B [2]). In PNKD mice, caffeine increased the speed of locomotion in the first 10 min post-injection prior to the onset of a measurable dystonic phenotype ( Figure 4D [3]), which was again associated with enhanced ACh delta power ( Figure 4B-D [2]). As dystonic movements developed and became more severe and long-lasting, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Invasive methods, such as deep brain stimulation, are useful in some but not all cases. Though most commonly idiopathic, many genetic mutations have been shown to cause dystonia [2, 3]. Animal models that have mutations in several of these genes have been developed and offer new insights into its pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

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Cholinergic Transmission in an Inducible Transgenic Mouse Model of Paroxysmal Dystonia

Scarduzio,

Jaunarajs,

Standaert

2024

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cholinergic Transmission in an Inducible Transgenic Mouse Model of Paroxysmal Dystonia

Scarduzio,

Jaunarajs,

Standaert

2024

Preprint

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Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

Wilson,

Jiang,

Desai

et al. 2024

Preprint

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BackgroundParoxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated aDrosophilamodel of a PxD-linked mutation causing BK potassium channel gain- of-function (BK GOF), and showed that BK GOF perturbs movement inDrosophilaby disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear.ObjectiveTo identify pharmacological suppressors of motor defects caused by BK GOF.MethodsUsing adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity ofDrosophilalarval motor circuits driving peristalsis and turning behaviors.ResultsWe found that inhibitors of acetylcholinesterase – a protein that degrades acetylcholine in cholinergic synapses – partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae.ConclusionsOur findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle thatDrosophilacan be utilised for screens to uncover putative drug treatments for involuntary movement disorders.

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Dystonia genes and their biological pathways

Cited by 2 publications

References 154 publications

Cholinergic Transmission in an Inducible Transgenic Mouse Model of Paroxysmal Dystonia

Cholinergic Transmission in an Inducible Transgenic Mouse Model of Paroxysmal Dystonia

Pharmacological rescue of motor circuit dysfunction in aDrosophilamodel of paroxysmal dyskinesia

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