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The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia

AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and...

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Autores principales: Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin‐Dušić, Zorana, Brkljačić, Jelena, Miljević, Čedo, Nikolić‐Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel F., Ingelman‐Sundberg, Magnus, Jukić, Marin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108232/
https://www.ncbi.nlm.nih.gov/pubmed/36536486
http://dx.doi.org/10.1111/nan.12867
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author Milosavljević, Filip
Brusini, Irene
Atanasov, Andrea
Manojlović, Marina
Vučić, Marija
Oreščanin‐Dušić, Zorana
Brkljačić, Jelena
Miljević, Čedo
Nikolić‐Kokić, Aleksandra
Blagojević, Duško
Wang, Chunliang
Damberg, Peter
Pešić, Vesna
Tyndale, Rachel F.
Ingelman‐Sundberg, Magnus
Jukić, Marin M.
author_facet Milosavljević, Filip
Brusini, Irene
Atanasov, Andrea
Manojlović, Marina
Vučić, Marija
Oreščanin‐Dušić, Zorana
Brkljačić, Jelena
Miljević, Čedo
Nikolić‐Kokić, Aleksandra
Blagojević, Duško
Wang, Chunliang
Damberg, Peter
Pešić, Vesna
Tyndale, Rachel F.
Ingelman‐Sundberg, Magnus
Jukić, Marin M.
author_sort Milosavljević, Filip
collection PubMed
description AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw‐print and beam‐walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild‐type mice were quantified by 9.4T gadolinium‐enhanced post‐mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam‐walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia‐like gait, clasping reflex and 5.6‐fold more paw‐slips in the beam‐walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
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spelling pubmed-101082322023-04-18 The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia Milosavljević, Filip Brusini, Irene Atanasov, Andrea Manojlović, Marina Vučić, Marija Oreščanin‐Dušić, Zorana Brkljačić, Jelena Miljević, Čedo Nikolić‐Kokić, Aleksandra Blagojević, Duško Wang, Chunliang Damberg, Peter Pešić, Vesna Tyndale, Rachel F. Ingelman‐Sundberg, Magnus Jukić, Marin M. Neuropathol Appl Neurobiol Original Articles AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw‐print and beam‐walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild‐type mice were quantified by 9.4T gadolinium‐enhanced post‐mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam‐walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia‐like gait, clasping reflex and 5.6‐fold more paw‐slips in the beam‐walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development. John Wiley and Sons Inc. 2023-01-17 2023-02 /pmc/articles/PMC10108232/ /pubmed/36536486 http://dx.doi.org/10.1111/nan.12867 Text en © 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological 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 Original Articles
Milosavljević, Filip
Brusini, Irene
Atanasov, Andrea
Manojlović, Marina
Vučić, Marija
Oreščanin‐Dušić, Zorana
Brkljačić, Jelena
Miljević, Čedo
Nikolić‐Kokić, Aleksandra
Blagojević, Duško
Wang, Chunliang
Damberg, Peter
Pešić, Vesna
Tyndale, Rachel F.
Ingelman‐Sundberg, Magnus
Jukić, Marin M.
The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title_full The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title_fullStr The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title_full_unstemmed The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title_short The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
title_sort humanised cyp2c19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108232/
https://www.ncbi.nlm.nih.gov/pubmed/36536486
http://dx.doi.org/10.1111/nan.12867
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