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

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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 neurons.

Original languageEnglish
Pages (from-to)354-61
Number of pages8
JournalBiological Psychiatry
Volume79
Issue number5
DOIs
Publication statusPublished - Mar 1 2016

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Keywords

  • Animals
  • Antiparkinson Agents
  • Daunorubicin
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced
  • Levodopa
  • Macaca fascicularis
  • Male
  • Neostriatum
  • Neurons
  • Oxidopamine
  • Parkinson Disease
  • Patch-Clamp Techniques
  • Proto-Oncogene Proteins c-fos
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

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. (2016). Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia. Biological Psychiatry, 79(5), 354-61. https://doi.org/10.1016/j.biopsych.2014.07.007