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Prenatal ontogeny of the dopamine-dependent neurobehavioral phenotype in Pitx3-deficient mice


Correspondence: Gale A. Kleven, as above.



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 analysed in fetal offspring derived from pregnant Pitx3ak/2J and C57BL/6J dams on the last 4 days before birth (E15-18 of a 19-day gestation). Using digital videography, we analysed: (i) behavioral state, by quantification of high- and low-amplitude movements, (ii) interlimb movement synchrony, a measure of the temporal relationship between spontaneous movements of limb pairs, (iii) facial wiping, a characteristic response to perioral tactile stimulation similar to the defensive response in human infants, and (iv) 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 (0.1 s) 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.