Role of striatal ΔFosB in L-Dopa-induced dyskinesias of parkinsonian nonhuman primates

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 Delta FosB 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 Delta FosB on L-Dopa responses, we induced transgenic Delta FosB overexpression in the striatum of parkinsonian nonhuman primates kept naive of L-Dopa treatment. Elevated Delta FosB 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 Delta FosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal Delta FosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD.