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; Benjamin Galet; Jonathan Pegon; Nicole Faucon Biguet; Anh Do Thi; Mark J Millan; Clotilde Mannoury la Cour; Rolando Meloni

doi:10.3389/fphar.2019.01233

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

Front Pharmacol. 2019 Oct 25:10:1233. doi: 10.3389/fphar.2019.01233. eCollection 2019.

Authors

Manuela Ingallinesi¹, Benjamin Galet¹, Jonathan Pegon¹, Nicole Faucon Biguet¹, Anh Do Thi¹, Mark J Millan², Clotilde Mannoury la Cour², Rolando Meloni¹

Affiliations

¹ Department of Biotechnology and Biotherapy, Institut du Cerveau et de la Moelle épinière (ICM) UPMC/INSERM U 1127/ CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France.
² Center for Innovation in Neuropsychiatry, Institut de Recherches Servier, Croissy sur Seine, France.

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.

Keywords: 6-hydroxydopamine 6-OHDA; Gpr88; L-3-4-dyhydroxyphenylalanine–induced dyskinesia; lentiviral vector; turning behavior.