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Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia

Abstract : 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 β-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 β-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing β-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 neuron
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Contributor : Benjamin Dehay Connect in order to contact the contributor
Submitted on : Tuesday, January 14, 2020 - 3:41:52 PM
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Michel Engeln, Matthieu Bastide, Estelle Toulmé, Benjamin Dehay, Mathieu Bourdenx, et al.. Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia. Biological Psychiatry, Elsevier, 2016, 79 (5), pp.354-361. ⟨10.1016/j.biopsych.2014.07.007⟩. ⟨inserm-02439355⟩



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