G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease

G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease

J Psychiatry Neurosci 2021;46(1):E44-E55 | PDF | Appendix

Benjamin Galet, PhD; Manuela Ingallinesi, PhD; Jonathan Pegon, MSc; Anh Do Thi, PhD; Philippe Ravassard, PhD; Nicole Faucon Biguet, PhD; Rolando Meloni, MD

Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target.

Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies.

Results: Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an “overload” hypothesis for the etiology of the psychiatric symptoms of Parkinson disease.

Limitations: Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types.

Conclusion: GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.

Submitted Oct. 17, 2019; Revised Feb. 3, 2020; Accepted Mar. 3, 2020; Early-released July 15, 2020

Acknowledgments: The lentiviral vectors were produced by the inhouse iVector facility. In vivo experiments were carried out in the PHENOPARC core facility, and histological procedures were performed at the HISTOMICS platform, both also situated in the ICM. The authors thank Annick Prigent for her time and advice related to the histological processing of the samples.

Affiliation: Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni).

Funding: The research leading to these results has received funding from the program Investissements d’avenir ANR-10-IAIHU-06. B. Galet was supported by a scholarship from the French Ministry of Research, awarded by the Brain-Cognition-Behavior Doctoral School of the Sorbonne University. The PHENOPARC Core is supported by 2 Investissements d’avenir grants (ANR-10-IAIHU-06 and ANR-11-INBS-0011-NeurATRIS) and the Fondation pour la Recherche Médicale. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Competing interests: None declared.

Contributors: B. Galet, P. Ravassard and R. Meloni designed the study. B. Galet, M. Ingallinesi, J. Pegon, A. Do Thi, N. Faucon Biguet and R. Meloni acquired the data, which B. Galet, A. Do Thi, N. Faucon Biguet and R. Meloni analyzed. B. Galet and R. Meloni wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.190171

Correspondence to: R. Meloni, Laboratory of Gene Regulation and Adaptive Behaviors (GRAB), Neurosciences Paris Seine, Sorbonne Université, 7 Quai Saint Bernard 75005, Paris France; rolando.meloni@upmc.fr