期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：37
页码：18664-18672
DOI：10.1073/pnas.1907810116
出版社：The National Academy of Sciences of the United States of America
摘要：Long-term dopamine (DA) replacement therapy in Parkinson’s disease (PD) leads to the development of abnormal involuntary movements known as l -Dopa–induced dyskinesia (LID). The transcription factor ΔFosB that is highly up-regulated in the striatum following chronic l -Dopa exposure may participate in the mechanisms of altered neuronal responses to DA generating LID. To identify intrinsic effects of elevated ΔFosB on l -Dopa responses, we induced transgenic ΔFosB overexpression in the striatum of parkinsonian nonhuman primates kept naïve of l -Dopa treatment. Elevated ΔFosB levels led to consistent appearance of LID since the initial acute l -Dopa tests. In line with this motor response, striatal projection neurons (SPNs) responded to DA with changes in firing frequency that reversed at the peak of the motor response, and these unstable SPN activity changes in response to DA are typically associated with the emergence of LID. Transgenic ΔFosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal ΔFosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD..
