pNR2B mediates the role of Fyn kinase in levodopa induced dyskinesia in a mouse model of Parkinson?s disease

GERSHANIK, OSCAR; ISAJA, LUCIANA; DAMIANICH, ANA; BORDONE, MELINA; FERRARIO, JUAN E.; SANZ-BLASCO, SARA

Paris

Congreso; ISN international meeting; 2017

Background: Levodopa (L-DOPA) induced dyskinesia (LID) is one of the undesired side effects of Parkinson?s disease (PD) treatment. To reduce the development of LID without affecting the positive restorative effect of dopamine stimulation is one of the greatest challenge in this area. We have previously explored the pathway Pleiotrophin/RPTP ζ/b/Fyn at the postsynaptic density complex and found that Fyn KO mice developed less LID than WT littermates. Fyn kinase modulates the NMDA receptor through phosphorylation of the NR2B subunit and this could explain the role of Fyn in LID.Objective: The main goal of this work is to demonstrate the direct relation between Fyn and NMDA receptors in a paradigm of dyskinesia. Methods: We lesioned Fyn KO and WT mice with 6-OHDA and treated daily with L-DOPA to model LID. Postmortem, dopaminergic denervation was confirmed by immunodetection of TH in the SNpc and several molecular markers were determined in the striatum by Western blot. Remarkably, the amount and phosphorylation status of NR2B subunit of NMDA. Results: In WT mice we found, as expected, upregulated FosB and pERK, both previously reported markers of LID, while Fyn-KO mice showed a significant reduction of LID accompanied by a downregulation of FosB and NR2B phosphorylation.Conclusion: pNR2B is downregulated in dyskinetic Fyn-KO mice what can explain a reduced NMDA signaling and therefore the observed reduced dyskinesia. Therefore, Fyn would be an attractive target to modify the NMDA signaling and a promising treatment to modulate LID without affecting the therapeutic efficacy of L-DOPA in PD.