Knock-Down of GPR88 in the Dorsal Striatum Alters the Response of Medium Spiny Neurons to the Loss of Dopamine Input and L-3-4-Dyhydroxyphenylalanine.

Manuela Ingallinesi,Mark J Millan,Benjamin Galet,Rolando Meloni,Anh Do Thi,Nicole Faucon Biguet,Jonathan Pegon,Clotilde Mannoury La Cour

doi:10.3389/fphar.2019.01233

Abstract

The effects of L-3-4-dyhydroxyphenylalanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson’s disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search for new treatments. The orphan G protein-coupled receptor 88 (Gpr88) represents a potential new target, as it is highly and almost exclusively expressed in the projecting gamma-Aminobutyric Acid-ergic (GABAergic) medium spiny neurons of the striatum, is implicated in motor activity, and is downregulated by 6-hydroxydopamine (6-OHDA) lesions, an effect that is reversed by L-DOPA. Thus, to evaluate Gpr88 as a potential target for the management of PD and L-DOPA–induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemiparkinsonism. Then, we investigated the effects of the KD-Gpr88 in the DA-deprived dorsal striatum on circling behavior and LID as well as on specific markers of striatal neuron activity. The KD-Gpr88 reduced the acute amphetamine-induced and increased L-DOPA–induced turning behavior. Moreover, it normalized the upregulated expression of striatal Gad67 and proenkephalin provoked by the 6-OHDA lesion. Finally, despite promoting ΔFosB accumulation, the KD-Gpr88 was associated neither with the upregulation of prodynorphin, which is causally linked to the severity of LID, nor with the aggravation of LID following chronic L-DOPA treatment in 6-OHDA–lesioned rats. These results thus justify further evaluation of Gpr88 as a potentially novel target for the management of PD as an alternative to L-DOPA therapy.

Highlights

The loss of dopamine (DA) input to the GABAergic striatal medium spiny neurons (MSNs) provokes an imbalance between the direct stimulatory striato-nigral and the indirect inhibitory striato-pallidal pathways responsible for movement initiation, thereby inducing the motor symptoms of Parkinson’s disease (PD) (Gerfen and Surmeier, 2011)
We assessed the impact of the G protein-coupled receptor 88 (Gpr88) knockdown (KD-Gpr88) on the turning behavior induced by Amph and L-DOPA, on the development of L-DOPA–induced dyskinesia (LID), and on the expression of striatal markers altered by the 6-OHDA lesion and the chronic L-DOPA treatment such as glutamic acid decarboxylase 67 (Gad67) as a marker of general MSN activity (Cenci et al, 1998) as well as Pdyn and Penk as markers of direct and indirect pathway specific activity, respectively (Cenci et al, 1998; Steiner and Gerfen, 1998)
We have found that the KD-Gpr88 in the dorsal DA-deafferented striatum produced a significant effect on motor activity in such a model of PD by attenuating the ipsilateral

Summary

INTRODUCTION

The loss of dopamine (DA) input to the GABAergic striatal medium spiny neurons (MSNs) provokes an imbalance between the direct stimulatory striato-nigral and the indirect inhibitory striato-pallidal pathways responsible for movement initiation, thereby inducing the motor symptoms of Parkinson’s disease (PD) (Gerfen and Surmeier, 2011). The precise role played by Gpr in motor regulation remains unclear, and its relevance as a target for PD treatment needs to be further evaluated To this end, using the unilateral 6-OHDA lesion as a model of PD, we locally inactivated Gpr in the dorsal DA-deprived striatum, a region that is associated with motor regulation (Do et al, 2013). We assessed the impact of the Gpr knockdown (KD-Gpr88) on the turning behavior induced by Amph and L-DOPA, on the development of LID, and on the expression of striatal markers altered by the 6-OHDA lesion and the chronic L-DOPA treatment such as Gad as a marker of general MSN activity (Cenci et al, 1998) as well as Pdyn and Penk as markers of direct and indirect pathway specific activity, respectively (Cenci et al, 1998; Steiner and Gerfen, 1998)

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

ETHICS STATEMENT