Pitx3 deficiency produces decreased dopamine signaling and induces motor deficits in Pitx3(−/−) mice

Abstract

Midbrain dopamine (DA) neurons are involved in cognition, control of motor activity, and emotion-related behaviors. Degeneration of DA neurons particularly in the substantia nigra is a hallmark of Parkinson's disease. The homeobox transcription factor, Pitx3, plays a critical role in the development, function, and maintenance of midbrain DA neurons. We found that in young adult Pitx3-null mice, Pitx3(−/−), there was decreased tyrosine hydroxylase staining, indicating a loss of DA neurons particularly in the substantia nigra. In addition, fast-scan cyclic voltammetry and microdialysis assays of DA release indicated that the lack of Pitx3 caused a significant reduction of striatal DA release. Tonic DA release was impaired more significantly than the phasic DA release induced by burst firing of DA neurons. Furthermore, behavioral tests revealed that Pitx3(−/−) mice displayed abnormal motor activities, including impaired motor coordination and decreased locomotion. In summary, these data provide further evidence that Pitx3 is specifically required for DA-related function and, if impaired, Pitx3 could contribute during the pathogenesis of Parkinson's disease.