Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia

Bido, Simone, Solari, Nicola, Indrigo, Marzia, D'Antoni, Angela, Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706, Morari, Michele and Fasano, Stefania ORCID: https://orcid.org/0000-0002-3696-7139 2015. Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia. Annals of Clinical and Translational Neurology 2 (6) , pp. 662-678. 10.1002/acn3.202

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Abstract

Objective Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates. Methods We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson's disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed. Results Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID. Interpretation Our results suggest that Ras-GRF1 is a promising target for LID therapy based on Ras-ERK signaling inhibition in the striatum.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Wiley-Blackwell
ISSN:	2328-9503
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	13 March 2015
Last Modified:	04 May 2023 14:59
URI:	https://orca.cardiff.ac.uk/id/eprint/81147

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