L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: Insights into regulation and function

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• 作者：Isabel Espadas ; Sanja Darmopil ; Eva Verga?o-Vera ; Oskar Ortiz ; Idaira Oliva ; Carlos Vicario-Abej¨®n ; Eduardo D. Mart¨ªn ; Rosario Moratalla
• 关键词：Parkinson's disease ; L-DOPA ; D1 and D2 dopamine receptors ; Pitx3 deficient aphakia mice ; Fast scan cyclic voltammetry ; Dopamine transporter (DAT) ; Aromatic-l-amino acid decarboxylase (AADC) ; Cylinder test ; Olfactory bulb transplants
• 刊名：Neurobiology of Disease
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：48
• 期：3
• 页码：271-281
• 全文大小：1751 K

文摘

Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons have been found in the striatum after dopamine depletion; however, little is known about the mechanism underlying their appearance or their functional significance. We previously showed an increase in striatal TH-ir neurons after l-DOPA treatment in mice with unilateral 6-OHDA lesions in the striatum. In the present study, we further examined the time-course and persistence of the effects of chronic l-DOPA treatment on the appearance and regulation of TH-ir neurons as well as their possible function. We found that the l-DOPA-induced increase in striatal TH-ir neurons is dose-dependent and persists for days after l-DOPA withdrawal, decreasing significantly 10 days after l-DOPA treatment ends. Using hemiparkinsonian D1 receptor knock-out (D1R^?/?) and D2 receptor knock-out (D2R^?/?) mice, we found that the D1R, but not the D2R, is required for the l-DOPA-induced appearance of TH-ir neurons in the dopamine-depleted striatum. Interestingly, our experiments in aphakia mice, which lack Pitx3 expression in the brain, indicate that the l-DOPA-dependent increase in the number of TH-ir neurons is independent of Pitx3, a transcription factor necessary for the development of mesencephalic dopaminergic neurons. To explore the possible function of l-DOPA-induced TH-ir neurons in the striatum, we examined dopamine overflow and forelimb use in l-DOPA-treated parkinsonian mice. These studies revealed a tight spatio-temporal correlation between the presence of striatal TH-ir neurons, the recovery of electrically stimulated dopamine overflow in the lesioned striatum, and the recovery of contralateral forelimb use with chronic l-DOPA treatment. Our results suggest that the presence of TH-ir neurons in the striatum may underlie the long-duration response to l-DOPA following withdrawal. Promotion of these neurons in the early stages of Parkinson's disease, when dopamine denervation is incomplete, may be beneficial for maintaining motor function.