Involvement of the bed nucleus of the stria terminalis in L-Dopa induced dyskinesia

Matthieu F Bastide,Qin Li,Erwan Bézard,François Georges,Éric C Dumont,Evelyne Doudnikoff,Pierre-Olivier Fernagut,Christelle Glangetas,Mathieu Bourdenx

doi:10.1038/s41598-017-02572-9

Abstract

A whole brain immediate early gene mapping highlighted the dorsolateral bed nucleus of the stria terminalis (dlBST) as a structure putatively involved in L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesia (LID), the debilitating side-effects of chronic dopamine replacement therapy in Parkinson’s disease (PD). dlBST indeed displayed an overexpression of ∆FosB, ARC, Zif268 and FRA2 only in dyskinetic rats. We thus hypothesized that dlBST could play a role in LID hyperkinetic manifestations. To assess the causal role of the dlBST in LID, we used Daun02 inactivation to selectively inhibit the electrical activity of dlBST ΔFosB-expressing neurons. Daun02 is a prodrug converted into Daunorubicin by ß-galactosidase. Then, the newly synthesized Daunorubicin is an inhibitor of neuronal excitability. Therefore, following induction of abnormal involuntary movements (AIMs), 6-OHDA rats were injected with Daun02 in the dlBST previously expressing ß-galactosidase under control of the FosB/ΔFosB promoter. Three days after Daun02 administration, the rats were tested daily with L-Dopa to assess LID. Pharmacogenetic inactivation of ∆FosB-expressing neuron electrophysiological activity significantly reduced AIM severity. The present study highlights the role of dlBST in the rodent analog of LID, offering a new target to investigate LID pathophysiology.

Highlights

Consistent with previous observations in the basal ganglia, we found an increased expression of the dopaminergic D1 receptor (D1R) protein in the dorsolateral bed nucleus of the stria terminalis (dlBST) of dyskinetic rats (Fig. 1C), which co-localized with ∆FosB (Fig. 1D)
Using in vivo single-unit extracellular recordings, we demonstrate that intra-dlBST injection of Daunorubicin (Fig. 2A,B) induced a 60% decrease in the number of evoked spikes in response to insular Ctx stimulation
One way Anova followed with 2 representative insets indicating the respective sites with white arrows. (C) Quantitative analysis of inhibitions induced by Daunorubicin infusion (Daunorubicin 4: 4 μg/μL; Daunorubicin 8: 8 μg/μL) on excitatory responses evoked by the insular cortex (INS Ctx) stimulation

Summary

Introduction

ΔFosB-expressing dlBST neurons in the rat model of LID in PD8–11 by inhibiting their electrical activity with the Daun02-inactivation method[8, 9, 12,13,14,15]. To directly assess a causal role of dlBST in AIM severity in the rodent analogue of dyskinesia, we inhibited the electrical activity of dlBST ∆FosB-expressing neurons using the selective Daun02/ß-galactosidase inactivation method.

Results

Conclusion