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

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...

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Autores principales: Tassone, Annalisa, Martella, Giuseppina, Meringolo, Maria, Vanni, Valentina, Sciamanna, Giuseppe, Ponterio, Giulia, Imbriani, Paola, Bonsi, Paola, Pisani, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291835/
https://www.ncbi.nlm.nih.gov/pubmed/34173686
http://dx.doi.org/10.1002/mds.28698
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author Tassone, Annalisa
Martella, Giuseppina
Meringolo, Maria
Vanni, Valentina
Sciamanna, Giuseppe
Ponterio, Giulia
Imbriani, Paola
Bonsi, Paola
Pisani, Antonio
author_facet Tassone, Annalisa
Martella, Giuseppina
Meringolo, Maria
Vanni, Valentina
Sciamanna, Giuseppe
Ponterio, Giulia
Imbriani, Paola
Bonsi, Paola
Pisani, Antonio
author_sort Tassone, Annalisa
collection PubMed
description 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(+/−) 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(+/−) 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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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spelling pubmed-92918352022-07-20 Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia Tassone, Annalisa Martella, Giuseppina Meringolo, Maria Vanni, Valentina Sciamanna, Giuseppe Ponterio, Giulia Imbriani, Paola Bonsi, Paola Pisani, Antonio Mov Disord Regular Issue Articles 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(+/−) 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(+/−) 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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society John Wiley & Sons, Inc. 2021-06-26 2021-12 /pmc/articles/PMC9291835/ /pubmed/34173686 http://dx.doi.org/10.1002/mds.28698 Text en © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Regular Issue Articles
Tassone, Annalisa
Martella, Giuseppina
Meringolo, Maria
Vanni, Valentina
Sciamanna, Giuseppe
Ponterio, Giulia
Imbriani, Paola
Bonsi, Paola
Pisani, Antonio
Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title_full Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title_fullStr Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title_full_unstemmed Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title_short Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia
title_sort vesicular acetylcholine transporter alters cholinergic tone and synaptic plasticity in dyt1 dystonia
topic Regular Issue Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291835/
https://www.ncbi.nlm.nih.gov/pubmed/34173686
http://dx.doi.org/10.1002/mds.28698
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