title: 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 neurons.
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Engeln
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Matthieu F
authors.initials: MF
authors.lastname: Bastide
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Toulmé
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Doudnikoff
authors.affiliation: China Academy of Medical Sciences, Institute of Laboratory Animal Sciences, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Gross
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Boué-Grabot
authors.affiliation: Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France. Electronic address: pierre-olivier.fernagut@u-bordeaux.fr.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D008297:Male; D017072:Neostriatum / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000008:administration & dosage; D010300:Parkinson Disease / Q000150:complications*; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C576267:N-(4''-(galactopyranosyl)-3''-nitrobenzyloxycarbonyl)daunomycin; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D007980:Levodopa; D016627:Oxidopamine; D003630:Daunorubicin
keywords: Daun02; Dyskinesia; Electrophysiology; FosB; Monkey; Parkinson’s disease