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Molecular and Cellular Biology, August 2001, p. 5321-5331, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5321-5331.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Katrin A. Mooslehner,1,* Pok Man Chan,1,2 Weiming Xu,3 Lizhi Liu,3 Claire Smadja,1,dagger Trevor Humby,1 Nicholas D. Allen,1 Lawrence S. Wilkinson,1 and Piers C. Emson1

The Babraham Institute, Neurobiology Programme, Babraham, Cambridge CB2 4AT,1 Department of Zoology, University of Cambridge, Cambridge CB2 3EJ,2 and The Rayne Institute, University College London, London WCIE 6JJ,3 United Kingdom

Received 13 March 2001/Accepted 8 May 2001

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.

* Corresponding author. Mailing address: Laboratories of Molecular and Cognitive Neuroscience, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. Phone: 44-1223-496502. Fax: 44-1223-496022. E-mail: katrin.mooslehner{at}bbsrc.ac.uk.

dagger Present address: The Laboratory of Neuropharmacology, JE MESR 92-372, Faculte de Pharmacie, Châtenay-Malabry, France.

Molecular and Cellular Biology, August 2001, p. 5321-5331, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5321-5331.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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