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The humanised CYP2C...
The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
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- Milosavljević, Filip (author)
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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- Brusini, Irene (author)
- KTH,Medicinsk avbildning,Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Huddinge, Sweden
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- Atanasov, Andrea (author)
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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- Manojlović, Marina (author)
- Karolinska Institutet
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- Vučić, Marija (author)
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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- Oreščanin-Dušić, Zorana (author)
- Institute for Biological Research "Siniša Stanković" – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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- Brkljačić, Jelena (author)
- Institute for Biological Research "Siniša Stanković" – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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- Miljević, Čedo (author)
- Department of Psychiatry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Institute for Mental Health, Belgrade, Serbia
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- Nikolić-Kokić, Aleksandra (author)
- Institute for Biological Research "Siniša Stanković" – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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- Blagojević, Duško (author)
- Institute for Biological Research "Siniša Stanković" – National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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- Wang, Chunliang, 1980- (author)
- KTH,Medicinsk avbildning
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- Damberg, Peter (author)
- Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, Solna, Sweden
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- Pešić, Vesna (author)
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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- Tyndale, Rachel F. (author)
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
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- Ingelman-Sundberg, Magnus (author)
- Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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- Jukić, Marin M. (author)
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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(creator_code:org_t)
- 2023-01-17
- 2023
- English.
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In: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 49:1
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Keyword
- animal models
- cerebellar ataxia
- cerebellum
- cytochrome P-450 Cyp2c19
- movement disorders
- neuroimaging
- transgenic mice
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Milosavljević, F ...
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Brusini, Irene
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Atanasov, Andrea
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Manojlović, Mari ...
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Vučić, Marija
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Oreščanin-Dušić, ...
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Brkljačić, Jelen ...
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Miljević, Čedo
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Nikolić-Kokić, A ...
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Blagojević, Dušk ...
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Wang, Chunliang, ...
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Damberg, Peter
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Pešić, Vesna
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Tyndale, Rachel ...
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Ingelman-Sundber ...
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Jukić, Marin M.
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Radiology Nuclea ...
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Neuropathology a ...
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Royal Institute of Technology
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Karolinska Institutet