BACKGROUND:ΔFosB is a surrogate marker of L-dopa-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-dopa long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown.METHODS:We used the Daun02 prodrug-inactivation method associated with lentiviral expression of ß-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability.RESULTS:We first show that daunorubicin, the active product of Daun02 metabolism by ß-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing ß-galactosidase upon D1 dopamine receptor stimulation. We then demonstrate that the selective, and reversible, inhibition of FosB/ΔFosB-expressing striatal neurons with Daun02 decreases the severity of LID while improving the beneficial effect of L-dopa.CONCLUSIONS:These results establish that FosB/ΔFosB accumulation ultimately results in altered neuronal electrical properties sustaining maladaptive circuits leading not only to LID but also to a blunted response to L-dopa. These findings further reveal that targeting dyskinesia can be achieved without reducing the antiparkinsonian properties of L-dopa when specifically inhibiting FosB/ΔFosB-accumulating neurons.