There are several naturally occurring spontaneous mutations in rodents that are of particular interest in PD. Spontaneous rodent models include the weaver, lurcher, reeler, Tshrhyt, tottering, and coloboma mice and the AS/AGU and circling (ci) rat. These models possess unique characteristics that may provide insight into neurodegener-ative processes of PD and related disorders. Several of these spontaneous rodent models display altered dopaminergic function or neurodegeneration, and have deficits in motor behavior (133). For example, the weaver mouse displays cell death of dopaminergic neurons, whereas the tottering mouse displays tyrosine hydroxylase hyper-innervation. The AS/AGU rat is a spontaneous model characterized by progressive rigidity, staggering gait, tremor, and difficulty in initiating movements (134). This strain arises from a recessive mutation within the gene encoding protein kinase C-gamma, suggesting another interesting gene implicated in neurodegeneration (135,136) affecting both the dopaminergic and serotonergic systems (135). Microdialysis in the AS/AGU rat model has revealed that even prior to dopaminergic neuronal cell death, there is dysfunction in dopaminergic neurotransmission that correlates with behavioral deficits. Another potentially interesting rodent model is the circling (ci) rat (137). This animal model displays spontaneous rotational behavior, as a result of an imbalance in dopaminergic neurotransmission despite the absence of asymmetric nigral cell death.
Another naturally occurring mutation is the aphakia mouse. This mutation affects a gene called Pitx3, which is a developmentally regulated homeobox containing transcription factor necessary for the establishment of midbrain dopaminer-gic neurons (138). Mice carrying mutations in Pitx3 display behavioral and neurochemical characteristics similar to the anatomical and functional deficits seen in PD, including cell loss in the substantia nigra dopaminergic neurons, a feature not seen in most transgenic mouse lines (139). The deficits in motor behavior can be rescued with levodopa replacement therapy. These mice demonstrate the importance of developmental factors for midbrain dopaminergic neurons and could reveal key therapeutic targets for treating PD (140).
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