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

Michel Engeln, Matthieu F. Bastide, Estelle Toulmé, Benjamin Dehay, Mathieu Bourdenx, Evelyne Doudnikoff, Qin Li, Christian E. Gross, Eric Boué-Grabot, Antonio Pisani, Erwan Bezard, Pierre Olivier Fernagut

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - 2014

Keywords

  • Daun02
  • dyskinesia
  • electrophysiology
  • FosB
  • monkey
  • Parkinson's disease

ASJC Scopus subject areas

  • Biological Psychiatry

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    Engeln, M., Bastide, M. F., Toulmé, E., Dehay, B., Bourdenx, M., Doudnikoff, E., Li, Q., Gross, C. E., Boué-Grabot, E., Pisani, A., Bezard, E., & Fernagut, P. O. (Accepted/In press). Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-Dopa-Induced Dyskinesia. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2014.07.007