L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: insights into regulation and function (CROSBI ID 188254)
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Espadas, Isabel ; Darmopil, Sanja ; ... ; Moratalla, Rosario
engleski
L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: insights into regulation and function
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.
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
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Temeljne medicinske znanosti, Biologija