Matthieu Bastide, Erwan Bézard dans Biological Psychiatry

Inhibiting Lateral Habenula Improves L-DOPA-induced Dyskinesia.
Bastide MF, de la Crompe B, Doudnikoff E, Fernagut PO, Gross CE, Mallet N, Boraud T, Bézard E.
Biol Psychiatry. 2014 Sep 9. pii: S0006-3223(14)00674-X. doi: 10.1016/j.biopsych.2014.08.022

Inhibiting Lateral Habenula improves L-Dopa induced dyskinesia We previously identified the Lateral Habenula (LHb) as potentially involved in L-dopa-induced dyskinesia (LID) based on its strong transcriptional response to L-Dopa in dyskinetic rats, as shown with an overexpression of ∆FosB, ARC and Zif268 (Bastide et al., Neurobiol Dis (2014);62:179-192). Interestingly, in the early 90’s, 2-deoxyglucose (2-DG) seminal studies showed that LHb stood up as a strongly affected non-basal ganglia nucleus displaying a dramatic increase in 2-DG accumulation in parkinsonism (Mitchell et al., Neuroscience (1989);32:213-226). To investigate the role of LHb neurons in LID, we used the daun02 inactivation method . In this study, we demonstrate that LHb displayed a LID-related pathological activity at different functional levels including metabolic, electrophysiological and ∆FosB-related transcriptional readouts.

Altogether, those data demonstrate that LHb neuronal activity in response to L-Dopa is related to LID manifestation. We show that firing frequency of LHb neurons significantly increased in dyskinetic rats, together with an increased expression of the dopaminergic D1 receptor in ∆FosB-positive neurons.

Then, using Daun02-driven inactivation, we demonstrate that the selective silencing of LHb ∆FosB-expressing neurons both alleviates LID severity and enhances the L-Dopa antiparkinsonian action, indicating an involvement of LHb both in LID expression and in the antiparkinsonian effect of L-Dopa. Taken altogether our results highlight a key role of LHb in the genesis of dyskinesia manifestation outside of the basal ganglia.

Erwan Bézard: Director of IMN

1er auteur

Matthieu F Bastide defended his thesis in septembre 2014 in the team of Christian Gross.