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

Abstract

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.

An ecologically relevant guinea pig model of fetal behavior

“…Similar to prior studies with mice,[29, 43] alternation of high and low amplitude bouts of movement separated by brief periods of quiescence (2–3s) were observed in all fetal subjects. With the exception of week 9, where low amplitude states averaged 2–3 min in length (Table 2), multiple state transitions were observed for all fetuses at each gestational age.…”

“…This pattern of increases across gestation followed by a decrease prior to birth has been reported for numerous mammalian species, including humans. [6, 28, 29, 43, 46, 48–51]…”

“…[56] In the Pitx3 mouse, where nigrostriatal dopamine neurons fail to differentiate, similar disruptions to the synchronous profiles were also observed. [5, 43, 57] Studies detailing the development of cortical activity and organization in the guinea pig revealed emergence between weeks 4 and 5, with differentiation of the cortical layers taking place between weeks 6 and 7, and descending motor control beginning at the end of week 7. [58–64] These transitions appear to correlate with changes in the synchrony profiles observed in this study (Figure 4).…”

Developmental pathways of motor dysfunction

“…Observations of fetal behavior for these cross‐sectional studies included a measure of spontaneous movement known as Interlimb Movement Synchrony. Interlimb Movement Synchrony quantifies the degree of temporal association between a limb pair (e.g., right and left forelimbs), and has been shown to be a sensitive developmental measure of spontaneous movement in the fetal rat (Kleven, Lane, & Robinson, ), mouse (Kleven, Joshi, Voogd, & Ronca, ; Kleven & Ronca, ), guinea pig (Bellinger, Lucas, & Kleven, ), and even preterm human infants (Key et al, ). Interlimb Movement Synchrony is scored from video playback and quantified by 0.1 s intervals in a range from 0.0 to 0.5 s. After standardization by movement rates, the resulting profiles depict relative rates of synchronous movement.…”

“…Similar to the studies of prenatal toxin exposures, fetal behavior in the Pitx3 mouse appears to be a good indicator of later adult (dys)function (Kleven et al, ). Deficits in coordinated movement have been identified well before birth in this mouse strain, including changes in organization of spontaneous movement such as specific patterns of reduction in Interlimb Movement Synchrony.…”