Mice with Very Low Expression of the Vesicular Monoamine Transporter 2 Gene Survive into Adulthood: Potential Mouse Model for Parkinsonism

Mooslehner, K. A., Chan, P. M., Xu, W. M., Liu, L. Z., Smadja, C., Humby, Trevor ORCID: https://orcid.org/0000-0002-1840-1799, Allen, Nicholas Denby ORCID: https://orcid.org/0000-0003-4009-186X, Wilkinson, Lawrence Stephen ORCID: https://orcid.org/0000-0002-9337-6124 and Emson, P. C. 2001. Mice with Very Low Expression of the Vesicular Monoamine Transporter 2 Gene Survive into Adulthood: Potential Mouse Model for Parkinsonism. Molecular and Cellular Biology 21 (16) , pp. 5321-5331. 10.1128/MCB.21.16.5321-5331.2001

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Abstract

We have created a transgenic mouse with a hypomorphic allele of the vesicular monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive into adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of the monoamine neurotransmitters below potentially toxic thresholds. Homozygous mice show large reductions in brain tissue monoamines, motor impairments, enhanced sensitivity to dopamine agonism, and changes in the chemical neuroanatomy of the striatum that are consistent with alterations in the balance of the striatonigral (direct) and striatopallidal (indirect) pathways. The VMAT2-deficient KA1 mice are also more vulnerable to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in terms of nigral dopamine cell death. We suggest that the mice may be of value in examining, long term, the insidious damaging consequences of abnormal intracellular handling of monoamines. On the basis of our current findings, the mice are likely to prove of immediate interest to aspects of the symptomatology of parkinsonism. They may also, however, be of use in probing other aspects of monoaminergic function and dysfunction in the brain, the latter making important contributions to the pathogenesis of schizophrenia and addiction.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Psychology Neuroscience and Mental Health Research Institute (NMHRI) Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	B Philosophy. Psychology. Religion > BF Psychology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0270-7306/ (accessed 25/02/2014)
Publisher:	American Society for Microbiology
ISSN:	0270-7306
Date of First Compliant Deposit:	30 March 2016
Last Modified:	05 May 2023 02:52
URI:	https://orca.cardiff.ac.uk/id/eprint/35351

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