Mouse models with prenatal alterations in dopaminergic functioning can provide new opportunities to identify fetal behavioral abnormalities and the underlying neural substrates dependent on dopamine. In this study, we tested the hypothesis that prenatal loss of nigrostriatal function is associated with fetal akinesia, or difficulty initiating movement. Specific behaviors were analyzed in fetal offspring derived from pregnant Pitx3ak/2J and C57BL/6J dams on the last four days before birth (E15–18 of a 19-day gestation). Using digital videography, we analyzed: (a) Behavioral State, by quantification of high and low amplitude movements, (b) Interlimb Movement Synchrony, a measure of the temporal relationship between spontaneous movements of limb pairs, (c) Facial Wiping, a characteristic response to perioral tactile stimulation similar to the defensive response in human infants, and (d) Oral Grasp of a non-nutritive nipple, a component of suckling in the human infant. Pitx3 mutants showed a selective decrease in Interlimb Movement Synchrony rates at the shortest (0.1s) temporal interval coupled with significantly increased latencies to exhibit Facial Wiping and Oral Grasp. Collectively, our findings provide evidence that the primary fetal neurobehavioral deficit of the Pitx3 mutation is akinesia related to nigrostriatal damage. Other findings of particular interest were the differences in neurobehavioral functioning between C57BL/6J and Pitx3 heterozygous subjects, suggesting the two groups are not equivalent controls. These results further suggest that fetal neurobehavioral assessments are sensitive indicators of emerging neural dysfunction, and may have utility for prenatal diagnosis.

Studies of fetal rodents have provided evidence that early emerging behaviors, such as the suckling response, are dependent on the developing dopaminergic system. Although connections have been made between manipulations of dopamine and altered behavioral responses, the specific neural pathways involved have yet to be discovered. In this study we examined the neurobehavioral output of the nigrostriatal pathway, using the Pitx3ak/2J mouse model (Pitx3). Used extensively in the study of Parkinson's disease, the Pitx3 mouse has very specific prenatal loss of dopaminergic neurons solely in the nigrostriatal pathway. Due to this specificity, we hypothesized that behavioral deficits specific to the nigrostriatal pathway would be reversed with administration of the dopamine precursor 3,4-dihydroxyphenylalanine (L-Dopa). To test this hypothesis, homozygous mutant and heterozygous control fetal subjects were administered one of four doses (0, 25, 50, or 75 mg/kg) of L-Dopa on the day before birth. Quantification of fetal behavior was scored from video recordings of behavioral observations. The behavioral measures used were: (a) spontaneous movement activity, (b) state organization, from quantifications of high and low amplitude movements, (c) Interlimb Movement Synchrony, a measure of limb coordination, and (d) Oral Grasp, similar to a newborn infant suckling response. Specific behavioral deficits observed in the Pitx3 mutants were reversed by L-Dopa administration in a dose-dependent manner. However, different deficits required dissimilar doses for reversal, suggesting that some early emerging behaviors may be more sensitive to the administration of L-Dopa. Taken together, this study provides valuable information about prenatal behaviors dependent on the nigrostriatal pathway.