L-dopa reverses behavioral deficits in the Pitx3 mouse fetus.

Abstract

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.

An ecologically relevant guinea pig model of fetal behavior

“…[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).…”