PhD: Matthieu Bastide

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

Defended on September 18, 2014.

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.

Keywords: Parkinson’s disease; L-Dopa induced dyskinesia; immediate early genes; stereology; 2-deoxyglucose; electrophysiology; daun02; rats; macaques

 

Publications:

PSD-95 expression controls L-Dopa dyskinesia. Matthieu Bastide and Erwan Bezard. February 2013. Médecine et Sciences. Vol. 29(2), pp. 139-141

Immediate-early genes expression in structures outside the basal ganglia is associated to L-dopa induced dyskinesia.
M. F. Bastide, S. Dovero, G. Charron, G. Porras, C. E. Gross, P. O. Fernagut and E. Bezard
February 2014. Neurobiology of Disease. Vol. 62, pp. 179-192

Basal ganglia circuitry models of L-DOPA-induced dyskinesia.
W. K. D. Ko, M. F. Bastide and E. Bezard
Book chapter of Levodopa-induced dyskinesia in Parkinson’s disease.

Selective inactivation of striatal FosB-expressing neurons alleviates L-Dopa-induced dyskinesia.
M. Engeln*, M. F. Bastide*, E. Toulmé, B. Dehay, Q. Li, C. E Gross, E. Boué-Grabot, A. Pisani, E. Bezard, P. O. Fernagut 
* M.Engeln and M. F. Bastide should be considered as co-first authors.
July 2014. Biological Psychiatry.

Inhibiting Lateral Habenula improves L-Dopa induced dyskinesia.
M.F. Bastide, B. de la Crompe, E. Doudnikoff, P. O. Fernagut, C.E. Gross, N. Mallet, T. Boraud, E. Bezard
In revision

NELF-mediating RNA Polymerase II stalling controls L-Dopa induced dyskinesia.
M.F. Bastide, N. Dutheil, C.E. Gross, Erwan Bezard.
Submitted

Invovlement of the Bed nucleus of the stria terminalis in L-Dopa induced dyskinesia.
M.F. Bastide, C. Glangetas, C. Di Prospero, E. Hawken, M. Bourdenx, E. Doudnikoff, P. O. Fernagut, C.E. Gross, F. Georges, E.C. Dumont, E. Bezard.
In preparation.

Pathophysiology of L-Dopa-induced dyskinesia in Parkinson’s disease
M.F. Bastide, W. Meissner, M. Bourdenx, T. Thiollier, M. Engeln, S. Navailles, P. De Deurwaerdère, J. A. Stoessl, N. Simola, M. Morelli, B. Picconi, L. Groc, M.C. Rodriguez, C. E. Gross, E. V. Gurevich, M. Quik, M. Morari, S. Fasano, R. Brambilla, M. Mellone, F. Gardoni, E. Tronci, M. Carta, M. Feyder, G. Fisone, D. Guehl, P. O. Fernagut, A. Cenci and E. Bezard 
In preparation.

Progressive nigrostriatal neurodegeneration associated with α-synuclein spreading and pathology induced by AAV-mediated overexpression of mutant synuclein in mice, rats and marmosets. E. Bezard, S. Bido, M. F. Bastide, C. Piron, M. Engeln, M. Bourdenx, F. Georges, D. Scheller, A. Michel, T. Boraud, P.O. Fernagut, S. Dovero and B. Dehay
In preparation.

PhD committee

  • Jean-Antoine Girault
    Chairman
  • Jocelyne Caboche
    Reviewer
  • Emmanuel Valjent
    Reviewer
  • Erwan Bézard
    Guest
  • Christian E. Gross
    thesis supervisor

Thesis supervisor

Christian Gross
MD-PhD
UMR 5293 CNRS

Université de Bordeaux 
Maître de conférence
Institut des Maladies Neurodégénératives

Last update: 18 September 2014