The kinase Fyn has an important role in NMDA receptor regulation in L-DOPA induced dyskinesia in a mouse model of Parkinson?s disease

FERRARIO, JUAN; GOMEZ, GIMENA; ISAJA, LUCIANA; GERSHANIK, OSCAR; BORDONE, MELINA; SANZ-BLASCO, SARA; BERNARDI, ALEJANDRA

Mar del Plata

Congreso; XXXII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2017

Sociedad Argentina de Neurociencias (SAN)

Levodopa (L-DOPA) induced dyskinesia (LID) is a side effect of Parkinson?s disease (PD) treatment. A great challenge is to reduce the development of LID without affecting the restorative effect of dopamine stimulation. It has been established that DA stimulation increases the phosphorylation at tyrosine 1472 of NR2B, regulatory subunit of NMDAR, which is one target of the Src kinase Fyn. Our aim is to address the role of Fyn in the NMDAR activation under L-DOPA stimulation in a mouse model of PD and the role of Fyn in the genesis of LID. We developed a model of PD in Fyn-KO and WT mice by induction of dopaminergic death by means of unilateral injection of 6-OHDA, and mice induced to developed LID by daily treatment with L-DOPA. Dopaminergic denervation was confirmed by immunodetection of TH in the SN. ΔFosB, TH, pNR2B were determined in the striatum byWB. Fyn-KO mice show a significant reduction in NR2B phosphorylation concomitant with a LID reduction, as shown by behavioural tests and ΔFosB levels reduction. In an independent set of experiments, WT mice were injected with 6-OHDA and randomly assigned to receive Amantadine (NMDA receptor antagonist), Saracatinib (Src kinase inhibitor), both, or vehicle together with L-DOPA. The three groups were compared in their ability to develop LID and the expression of molecular markers of LID.