Juvenile Deficits Revealed in the Pitx3 Model of Parkinson's Disease

Abstract

<p>Recent evidence has revealed connections between prenatal insults and the development of Parkinson's disease, a neurodegenerative disorder that affects motor function. In the Pitx3ak/2J mouse model, dopaminergic neurons in the substantia nigra do not differentiate thereby disrupting the developing nigrostriatal pathway (Hwang et aI., 2003). In humans, PITX3 alteration is highly correlated with an early onset of Parkinson's (Bergman et aI., in press). Because the Pitx3 mutation in mice has profound effects on early development, and humans with alterations in PITX3 often present with Parkinson's at younger ages, we hypothesize that behavioral testing of the Pitx3 mouse mutant should reveal deficits in juveniles and young adults, confirming Pitx3ak/2J as an early-onset mouse model for Parkinson's disease. Adult wild-type C57BL/6J, Pitx3 mutant mice, and rdl blind controls were tested longitudinally as juveniles at one month (P30) and as young adults at two months of age (P60) in an open field and pole climbing task. To confirm that alterations in behavior resulted from reduced striatal functioning, localized MRS data from the dorsal striatum were collected from both juvenile and adult mice. Because changes in the levels of neuronal metabolic markers in the basal ganglia have been suggestive of Parkinson's disease (Koga et aI., 2006; Rango et aI., 2006), concentrations of choline (Cho) and N-acetyl aspartate (NAA) were measured and analyzed at each age. Functional deficits (longer descent, increased rotation, and decreased rearing) and changes in striatal metabolites were detected at the earliest time point tested (P30), corresponding to juvenile development in humans. Together, these results affirm our hypothesis of early onset motor dysfunction in the Pitx3 mouse model of Parkinson's disease. Further study of this model may provide crucial information on the early emergence of this disease process and new insight into how developmental mechanisms may contribute to adult disease.</p><p>This presentation occurred at the Wright State University Campus-Wide Celebration of Research, Scholarship and Creative Activities on April 16, 2010</p>