Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-Dopa-Induced Dyskinesia (2014)
Biol Psychiatry. 2014 Jul 15. pii: S0006-3223(14)00506-X. doi: 10.1016/j.biopsych.2014.07.007.
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.
We used the Daun02 prodrug-inactivation method associated with lentiviral expression of ß-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.
We first show that daunorubicin, the active product of Daun02 metabolism by ß-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing ß-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.
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 © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.