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

Abstract

Significance l-Dopa–induced dyskinesia (LID) is a major complication of dopaminergic therapy in Parkinson’s disease. These involuntary movements have been associated with several molecular changes in the striatum, including increased levels of ΔFosB. However, whether ΔFosB upregulation plays a major role in the development of the primate LID or is an epiphenomenon of chronic l-Dopa treatment remains unknown. Using transgenic expression of ΔFosB in the striatum of parkinsonian primates, we show that elevated levels of ΔFosB lead to LID development in the absence of chronic l-Dopa exposure. The physiological and molecular changes associated with LID are also replicated in this model. These findings suggest that ΔFosB elevation is responsible for LID generation and that repressing its expression can have therapeutic value. 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.