Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia.
Biological Psychiatry. 2016-03-01; 79(5): 354-361
DOI: 10.1016/j.biopsych.2014.07.007
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1. Biol Psychiatry. 2016 Mar 1;79(5):354-361. doi: 10.1016/j.biopsych.2014.07.007.
Epub 2014 Jul 15.
Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates
L-DOPA-Induced Dyskinesia.
Engeln M(1), Bastide MF(1), Toulmé E(1), Dehay B(1), Bourdenx M(1), Doudnikoff
E(1), Li Q(2), Gross CE(1), Boué-Grabot E(1), Pisani A(3), Bezard E(1), Fernagut
PO(4).
Author information:
(1)University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France; National Centre for Scientific Research, Institut des Maladies
Neurodégénératives, Bordeaux, France.
(2)China Academy of Medical Sciences, Institute of Laboratory Animal Sciences,
Beijing, China.
(3)Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia, Istituto
di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
(4)University de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
France; National Centre for Scientific Research, Institut des Maladies
Neurodégénératives, Bordeaux, France. Electronic address:
.
Comment in
Biol Psychiatry. 2016 Mar 1;79(5):338-40.
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.
Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.biopsych.2014.07.007
PMID: 25146322 [Indexed for MEDLINE]