期刊
JOURNAL OF NEUROCHEMISTRY
卷 108, 期 3, 页码 621-633出版社
WILEY
DOI: 10.1111/j.1471-4159.2008.05831.x
关键词
bacterial artificial chromosome; l-DOPA-induced dyskinesia; mitogen- and stress-activated kinase 1; Parkinson's disease; striatum; transgenic mice
资金
- Swedish Research Council [20715, 13482, 14862]
- Parkinson Foundation in Sweden
- Wenner-Gren Foundations (GF) [ANR-05-NEUR-020]
- The Picower Foundation and USAMRAA/DOD [DAMD17-02-1-0705, W81XWH-05-1-0146]
In the dopamine-depleted striatum, extracellular signal-regulated kinase (ERK) signaling is implicated in the development of l-DOPA-induced dyskinesia. To gain insights on its role in this disorder, we examined the effects of l-DOPA on the state of phosphorylation of ERK and downstream target proteins in striatopallidal and striatonigral medium spiny neurons (MSNs). For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D-2 receptor (Drd2-EGFP mice) or the dopamine D-1 receptor (Drd1a-EGFP mice), which are expressed in striatopallidal and striatonigral MSNs, respectively. In 6-hydroxydopamine-lesioned Drd2-EGFP mice, l-DOPA increased the phosphorylation of ERK, mitogen- and stress-activated kinase 1 and histone H3, selectively in EGFP-negative MSNs. Conversely, a complete co-localization between EGFP and these phosphoproteins was observed in Drd1a-EGFP mice. The effect of l-DOPA was prevented by blockade of dopamine D-1 receptors. The same pattern of activation of ERK signaling was observed in dyskinetic mice, after repeated administration of l-DOPA. Our results demonstrate that in the dopamine-depleted striatum, l-DOPA activates ERK signaling specifically in striatonigral MSNs. This regulation may result in ERK-dependent changes in striatal plasticity leading to dyskinesia.
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