cNdufs2- (MCI-Park) mice were generated to inactivate Ndufs2 (NADH:ubiquinone oxidoreductase core subunit S2) specifically in dopaminergic neurons. Ndufs2 encodes a protein that contributes to the ubiquinone-binding site of mitochondrial complex I (MCI). Mice harboring a floxed allele of Ndufs2 (Ndufs2fl) were crossed with mice expressing Cre recombinase under the control of the Slc6a3 (dopamine transporter; DAT) promoter. cNdufs2- homozygous knock-out mice (Ndufs2fl/fl DATIREScre/+) manifest clear, levodopa-responsive parkinsonism that is attributable to MCI dysfunction, thus they are referred to as MCI-Park mice. In contrast to conventional Parkinson's disease (PD) models in which dopamine (DA) is depleted rapidly throughout the basal ganglia, the staging of pathology in these mice enables an assessment of how regional deficits in DA release are coupled to behavior. Some of the mutant pups are smaller than others. As dorsal striatal DA release declines to near detection thresholds around P30, homozygous knock-out animals lose the ability to perform an associative learning task that is thought to rely on DA-dependent striatal synaptic plasticity. Interestingly, this memory task is restored by systemic levodopa treatment (6 mg kg-1) at P30, but not by treatment later at P60. Although deficits in striatal motor learning are profound at P30, mice do not exhibit gross impairments in motor performance. That said, fine motor skills, as assessed by the time taken by mice to remove an adhesive from their forepaw, is significantly slower in homozygous mice at this age and becomes progressively worse with time. In contrast to the situation with the associative learning task, levodopa treatment improves the speed of adhesive removal regardless of age. By P40, open-field, exploratory behavior of homozygous mice begins to be interrupted by brief pauses, although the total distance travelled during the testing period is normal. Later, their open-field behavior becomes progressively more impaired and the total distance travelled begins to decrease. As expected of a disability rooted in dopaminergic signaling, levodopa treatment improves the performance of mice in this task. At around P60, knock-out mice exhibit only subtle impairments in gait when placed on a treadmill and many have a scruffy appearance. By P100, they have splayed hindlimbs, abnormal paw placement and alterations in stride when forced to ambulate on the treadmill. Levodopa ameliorates some, but not all, of these deficits. cNdufs2- mice become progressively more impaired with age, and begin dying of unknown causes around P90. Animals are said to exhibit a low body temperature. No significant differences have been observed between males and females. Mice that are homozygous for the floxed Ndufs2 allele (Ndufs2tm1.1Job) and wildtype for Cre are used as controls by the donating laboratory.
 Distribution of this double mutant strain (Stock No. 036313) was supported by the Michael J. Fox Foundation for Parkinson's Research.

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cNdufs2- (MCI-Park) mice were generated to inactivate Ndufs2 (NADH:ubiquinone oxidoreductase core subunit S2) specifically in dopaminergic neurons (Ndufs2fl/fl DATIREScre/+). Ndufs2 encodes a protein that contributes to the ubiquinone-binding site of mitochondrial complex I (MCI). Homozygous knock-out animals manifest clear, levodopa-responsive parkinsonism that is attributable to MCI dysfunction. In contrast to conventional Parkinson's disease (PD) models in which dopamine (DA) is depleted rapidly throughout the basal ganglia, the staging of pathology in these mice enables an assessment of how regional deficits in DA release are coupled to behavior.

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Heterozygous for Ndufs2<tm1.1Job>, Heterozygous for Slc6a3<tm1.1(cre)Bkmn>

Heterozygous for Ndufs2<tm1.1Job>, Wildtype for Slc6a3<tm1.1(cre)Bkmn>

Homozygous for Ndufs2<tm1.1Job>, Wildtype for Slc6a3<tm1.1(cre)Bkmn>

Wildtype for Ndufs2<tm1.1Job>, Heterozygous for Slc6a3<tm1.1(cre)Bkmn>

Wildtype for Ndufs2<tm1.1Job>, Wildtype for Slc6a3<tm1.1(cre)Bkmn>