L-Dopa Reverses Fetal Behavioral Deficits in the PITX3 Mouse Model of Parkinson's Disease

Abstract

<p>The genetically altered Pitx3ak/2J mouse is a model of Parkinson's disease in which over 50% of the dopaminergic neurons in the substantia nigra fail to differentiate prior to birth, leading to an 80% loss of dopaminergic functioning by adulthood. We have previously shown that prenatal behavioral deficits, such as alterations in oral grasping, facial wiping responses, and spontaneous limb movements, predict dysfunction in juvenile and adult Pitx3 mice. These adult deficits have been reversed with the dopamine precursor 3,4dihydroxyphenylalanine (L-DOPA), which is used in humans as a first-line treatment for Parkinson's disease. Because early behaviors such as the oral grasping and facial wiping responses are also dopamine-dependant, we hypothesized that L-DOPA would reverse functional deficits in the Pitx3 fetus. In order to test this hypothesis, pregnant Pitx3ak/2J (n=7) and wt C57BL/6J controls (n=7) were prepared on the day before birth (E18) using standard methods for direct fetal observation. After preparation, fetal subjects were externalized and observed for a 1 minute baseline period. LDOPA was administered to fetal subjects by intra-peritoneal injection in doses of 0, 25, 50, and 75 mg/kg. After a 15 minute period to allow for L-DOPA activation, spontaneous movement was observed for 4 minutes followed by a 1 minute presentation of an artificial nipple. All observations were recorded on (DV) video for later scoring of behavior. Analyses revealed L-DOPA reversal of deficits observed in the oral grasping response with the 75 mg/kg dose, documenting dopamine depletion as the major factor in behavioral deficits for the Pitx3 fetus. These results connecting prenatal dopaminergic systems and postnatal outcomes provide important insights into the origins of adult disease, laying the foundation for future studies improving diagnosis, treatment and possibly the prevention of Parkinson's disease.</p><p>This presentation occurred at the Wright State University Campus-Wide Celebration of Research, Scholarship and Creative Activities on April 8, 2011</p>