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

Biol Psychiatry. 2016 Mar 1;79(5):354-361. doi: 10.1016/j.biopsych.2014.07.007. Epub 2014 Jul 15.


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.

Keywords: Daun02; Dyskinesia; Electrophysiology; FosB; Monkey; Parkinson’s disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects*
  • Daunorubicin / administration & dosage
  • Daunorubicin / analogs & derivatives*
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / drug therapy*
  • Levodopa / adverse effects*
  • Macaca fascicularis
  • Male
  • Neostriatum / drug effects*
  • Neurons / drug effects*
  • Oxidopamine / administration & dosage
  • Parkinson Disease / complications*
  • Patch-Clamp Techniques
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / metabolism


  • Antiparkinson Agents
  • N-(4''-(galactopyranosyl)-3''-nitrobenzyloxycarbonyl)daunomycin
  • Proto-Oncogene Proteins c-fos
  • Receptors, Dopamine D1
  • Levodopa
  • Oxidopamine
  • Daunorubicin