Multifunctional approach of L-Dopa induced dyskinesia pathophysiology in Parkinson’s disease: From the striatum to the whole brain.

septembre 2014

Directeur(s) de thèse : Christian GROSS

Résumé de thèse

The gold standard treatment for Parkinson’s disease (PD) remains the dopamine precursor L-3,4-dihydroxyphenylalanine (L-Dopa). Long-term L-Dopa treatment systematically leads to abnormal involuntary movements (AIMs) called L-DOPA-induced dyskinesia (LID). These manifestations first led to investigate the neuronal dysfunctions in the motor regions of the basal ganglia and unravelled an overexpression of ΔFosB, ARC, Zif268 and FRA2 immediate-early genes (IEG) in the dopamine-depleted striatum of dyskinetic rats. However, other several dopaminoceptive structures, likely affected by the exogenously produced dopamine, have been neglected although they might play a key role in mediating LID. Hence, we assessed the expression of ΔFosB, ARC, FRA2 and Zif268 IEGs in the whole brain of dyskinetic rats compared to non-dyskinetic ones. Such approach shed light notably upon 9 structures located outside of the basal ganglia displaying an IEG overexpression. Among them, the dorsolateral bed nucleus of the stria terminalis (dlBST) and the lateral habenula (LHb) displayed a significant correlation between ∆FosB expression and LID severity. We therefore postulated that these structures might play a role in LID manifestation. Therefore, to assess dlBST and LHb casual roles upon LID severity, we inhibited the electrical activity of FosB/ΔFosB-expressing neurons using the selective Daun02/β-galactosidase inactivation method that we previously validated in a well known structure involve in LID: the striatum. Interestingly, the inhibition of ∆FosB-expressing dlBST and LHb neurons alleviated LID severity and increased the beneficial effect of L-Dopa in dyskinetic rats. Remarkably, BST involvement in LID was confirmed in the gold standard model of LID, the dyskinetic MPTP-lesioned macaque. Altogether, our results highlight for the first time the functional involvement of 2 structures outside of the basal ganglia in LID, offering new targets to innovative treatments of LID.