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

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.

ACKNOWLEDGMENTS

We thank Carlos de la Riva and Michael Hinton for their excellent technical assistance in generating and interpreting the HPLC data.

This work was funded by the Biotechnology and Biological Sciences Research Council, United Kingdom, and the Parkinson's Disease Society, United Kingdom (grant 3094 to P. C. Emson and L. S. Wilkinson). N. D. Allen is a BBSRC Advanced Fellow. All animals in this study were treated in accordance with the United Kingdom Animal (Scientific Procedures) Act of 1986.