Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: Potential mouse model for parkinsonism

We have created a transgenic mouse with a hypomorphic allele of the vesicul ar monoamine transporter 2 (Vmat2) gene by gene targeting. These mice (KA1) have profound changes in monoamine metabolism and function and survive int o adulthood. Specifically, these animals express very low levels of VMAT2, an endogenous protein which sequesters monoamines intracellularly into vesi cles, a process that, in addition to being important in normal transmission , may also act to keep intracellular levels of the monoamine neurotransmitt ers below potentially toxic thresholds. Homozygous mice show large reductio ns in brain tissue monoamines, motor impairments, enhanced sensitivity to d opamine agonism, and changes in the chemical neuroanatomy of the striatum t hat are consistent with alterations in the balance of the striatonigral (di rect) 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 damag ing consequences of abnormal intracellular handling of monoamines. On the b asis of our current findings, the mice are likely to prove of immediate int erest to aspects of the symptomatology of parkinsonism. They may also, howe ver, be of use in probing other aspects of monoaminergic function and dysfu nction in the brain, the latter making important contributions to the patho genesis of schizophrenia and addiction.