Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia

Mazère, Joachim; Dilharreguy, Bixente; Catheline, Gwénaëlle; Vidailhet, Marie; Deffains, Marc; Vimont, Delphine; Ribot, Bastien; Barse, Elodie; Cif, Laura; Mazoyer, Bernard; Langbour, Nicolas; Pisani, Antonio; Allard, Michèle; Lamare, F.; Guehl, Dominique; Fernandez, Philippe; Burbaud, Pierre

doi:10.1093/brain/awaa465

Cited by 23 publications

(16 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…64,65 VAChT represents a promising target to measure cholinergic deficits in dystonia patients. 66,67 Overall, our findings provide a direct demonstration of a significant alteration of the cholinergic transmission in the striatum of DYT1 mice, further adding to substantial evidence in support of the central role of ACh in DYT1 dystonia pathophysiology.…”

Section: Discussionsupporting

confidence: 68%

See 1 more Smart Citation

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Acetylcholine-mediated transmission plays a central role in the impairment of corticostriatal synaptic activity and plasticity in multiple DYT1 mouse models. However, the nature of such alteration remains unclear. Objective: The aim of the present work was to characterize the mechanistic basis of cholinergic dysfunction in DYT1 dystonia to identify potential targets for pharmacological intervention. Methods: We utilized electrophysiology recordings, immunohistochemistry, enzymatic activity assays, and Western blotting techniques to analyze in detail the cholinergic machinery in the dorsal striatum of the Tor1a +/À mouse model of DYT1 dystonia. Results: We found a significant increase in the vesicular acetylcholine transporter (VAChT) protein level, the protein responsible for loading acetylcholine (ACh) from the cytosol into synaptic vesicles, which indicates an altered cholinergic tone. Accordingly, in Tor1a +/À mice we measured a robust elevation in basal ACh content coupled to a compensatory enhancement of acetylcholinesterase (AChE) enzymatic activity.Moreover, pharmacological activation of dopamine D2 receptors, which is expected to reduce ACh levels, caused an abnormal elevation in its content, as compared to controls. Patch-clamp recordings revealed a reduced effect of AChE inhibitors on cholinergic interneuron excitability, whereas muscarinic autoreceptor function was preserved. Finally, we tested the hypothesis that blockade of VAChT could restore corticostriatal long-term synaptic plasticity deficits. Vesamicol, a selective VAChT inhibitor, rescued a normal expression of synaptic plasticity. Conclusions: Overall, our findings indicate that VAChT is a key player in the alterations of striatal plasticity and a novel target to normalize cholinergic dysfunction observed in DYT1 dystonia.

show abstract

Section: Discussionsupporting

confidence: 68%

“…Novel, selective VAChT Positron emission tomography (PET) ligands have been recently developed to measure cholinergic function in a number of conditions, including Parkinson's and Alzheimer's diseases 64,65 . VAChT represents a promising target to measure cholinergic deficits in dystonia patients 66,67 …”

Section: Discussionmentioning

confidence: 99%

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast to the other KI mice, the present study showed a significant reduction of the dorsolateral striatal ChIs in Dyt1 KI mice, consistent with the reduced trkA expression in postmortem tissues from older DYT1 dystonia patients ( Pappas et al, 2015 ). Moreover, a recent study using positron emission tomography (PET) suggests a decrease in VAChT expression in the posterior putamen and caudate nucleus of young DYT1 dystonia patients ( Mazere et al, 2021 ). On the other hand, Dyt1 KI mice showed normal levels of striatal cholinergic enzymes and TrkA.…”

Section: Discussionmentioning

confidence: 99%

Reversal of motor-skill transfer impairment by trihexyphenidyl and reduction of dorsolateral striatal cholinergic interneurons in Dyt1 ΔGAG knock-in mice

Yokoi

Dang

Zhang

et al. 2021

IBRO Neuroscience Reports

View full text Add to dashboard Cite

DYT-TOR1A or DYT1 early-onset generalized dystonia is an inherited movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, or abnormal postures. The majority of the DYT1 dystonia patients have a trinucleotide GAG deletion in DYT1/TOR1A . Trihexyphenidyl (THP), an antagonist for excitatory muscarinic acetylcholine receptor M1, is commonly used to treat dystonia. Dyt1 heterozygous ΔGAG knock-in (KI) mice, which have the corresponding mutation, exhibit impaired motor-skill transfer. Here, the effect of THP injection during the treadmill training period on the motor-skill transfer to the accelerated rotarod performance was examined. THP treatment reversed the motor-skill transfer impairment in Dyt1 KI mice. Immunohistochemistry showed that Dyt1 KI mice had a significant reduction of the dorsolateral striatal cholinergic interneurons. In contrast, Western blot analysis showed no significant alteration in the expression levels of the striatal enzymes and transporters involved in the acetylcholine metabolism. The results suggest a functional alteration of the cholinergic system underlying the impairment of motor-skill transfer and the pathogenesis of DYT1 dystonia. Training with THP in a motor task may improve another motor skill performance in DYT1 dystonia.

show abstract

“…This latter protocol is routinely performed in our center. 24,25 Each sequence lasted 6 minutes 21 seconds. The MPRAGE sequence was considered as the criterion standard for the volumetric measurements.…”

Section: Protocolmentioning

confidence: 99%

The Compressed Sensing MP2RAGE as a Surrogate to the MPRAGE for Neuroimaging at 3 T

et al. 2022

Self Cite

View full text Add to dashboard Cite

Objectives: The magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence provides quantitative T 1 maps in addition to high-contrast morphological images. Advanced acceleration techniques such as compressed sensing (CS) allow its acquisition time to be compatible with clinical applications. To consider its routine use in future neuroimaging protocols, the repeatability of the segmented brain structures was evaluated and compared with the standard morphological sequence (magnetization-prepared rapid gradient echo [MPRAGE]). The repeatability of the T 1 measurements was also assessed. Materials and Methods: Thirteen healthy volunteers were scanned either 3 or 4 times at several days of interval, on a 3 T clinical scanner, with the 2 sequences (CS-MP2RAGE and MPRAGE), set with the same spatial resolution (0.8-mm isotropic) and scan duration (6 minutes 21 seconds). The reconstruction time of the CS-MP2RAGE outputs (including the 2 echo images, the MP2RAGE image, and the T 1 map) was 3 minutes 33 seconds, using an open-source in-house algorithm implemented in the Gadgetron framework.Both precision and variability of volume measurements obtained from CAT12 and VolBrain were assessed. The T 1 accuracy and repeatability were measured on phantoms and on humans and were compared with literature.Volumes obtained from the CS-MP2RAGE and the MPRAGE images were compared using Student t tests ( P < 0.05 was considered significant). Results: The CS-MP2RAGE acquisition provided morphological images of the same quality and higher contrasts than the standard MPRAGE images. Similar intravolunteer variabilities were obtained with the CS-MP2RAGE and the MPRAGE segmentations. In addition, high-resolution T 1 maps were obtained from the CS-MP2RAGE. T 1 times of white and gray matters and several deep gray nuclei are consistent with the literature and show very low variability (<1%). Conclusions: The CS-MP2RAGE can be used in future protocols to rapidly obtain morphological images and quantitative T 1 maps in 3-dimensions while maintaining high repeatability in volumetry and relaxation times.

show abstract

Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia

Cited by 23 publications

References 65 publications

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia

Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia

Reversal of motor-skill transfer impairment by trihexyphenidyl and reduction of dorsolateral striatal cholinergic interneurons in Dyt1 ΔGAG knock-in mice

The Compressed Sensing MP2RAGE as a Surrogate to the MPRAGE for Neuroimaging at 3 T

Contact Info

Product

Resources

About