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 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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Corpus Striatum
Dyskinesias
Neurons
Galactosidases
Daunorubicin
Parkinson Disease
Antiparkinson Agents
Dopamine D1 Receptors
Prodrugs
Patch-Clamp Techniques
Haplorhini
Biomarkers
Brain

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., ... 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

Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia. / Engeln, Michel; Bastide, Matthieu F.; Toulmé, Estelle; Dehay, Benjamin; Bourdenx, Mathieu; Doudnikoff, Evelyne; Li, Qin; Gross, Christian E.; Boué-Grabot, Eric; Pisani, Antonio; Bezard, Erwan; Fernagut, Pierre Olivier.

In: Biological Psychiatry, Vol. 79, No. 5, 01.03.2016, p. 354-61.

Research output: Contribution to journalArticle

Engeln, M, Bastide, MF, Toulmé, E, Dehay, B, Bourdenx, M, Doudnikoff, E, Li, Q, Gross, CE, Boué-Grabot, E, Pisani, A, Bezard, E & Fernagut, PO 2016, 'Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia', Biological Psychiatry, vol. 79, no. 5, pp. 354-61. https://doi.org/10.1016/j.biopsych.2014.07.007
Engeln, Michel ; Bastide, Matthieu F. ; Toulmé, Estelle ; Dehay, Benjamin ; Bourdenx, Mathieu ; Doudnikoff, Evelyne ; Li, Qin ; Gross, Christian E. ; Boué-Grabot, Eric ; Pisani, Antonio ; Bezard, Erwan ; Fernagut, Pierre Olivier. / Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia. In: Biological Psychiatry. 2016 ; Vol. 79, No. 5. pp. 354-61.
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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.",
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author = "Michel Engeln and Bastide, {Matthieu F.} and Estelle Toulm{\'e} and Benjamin Dehay and Mathieu Bourdenx and Evelyne Doudnikoff and Qin Li and Gross, {Christian E.} and Eric Bou{\'e}-Grabot and Antonio Pisani and Erwan Bezard and Fernagut, {Pierre Olivier}",
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TY - JOUR

T1 - Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia

AU - Engeln, Michel

AU - Bastide, Matthieu F.

AU - Toulmé, Estelle

AU - Dehay, Benjamin

AU - Bourdenx, Mathieu

AU - Doudnikoff, Evelyne

AU - Li, Qin

AU - Gross, Christian E.

AU - Boué-Grabot, Eric

AU - Pisani, Antonio

AU - Bezard, Erwan

AU - Fernagut, Pierre Olivier

N1 - Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

KW - Animals

KW - Antiparkinson Agents

KW - Daunorubicin

KW - Disease Models, Animal

KW - Dyskinesia, Drug-Induced

KW - Levodopa

KW - Macaca fascicularis

KW - Male

KW - Neostriatum

KW - Neurons

KW - Oxidopamine

KW - Parkinson Disease

KW - Patch-Clamp Techniques

KW - Proto-Oncogene Proteins c-fos

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Dopamine D1

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.biopsych.2014.07.007

DO - 10.1016/j.biopsych.2014.07.007

M3 - Article

VL - 79

SP - 354

EP - 361

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 5

ER -