D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

Ermanno Florio; Marcello Serra; Robert G Lewis; Enikö Kramár; Michael Freidberg; Marcello Wood; Micaela Morelli; Emiliana Borrelli

doi:10.1016/j.isci.2022.105263

D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

iScience. 2022 Oct 4;25(10):105263. doi: 10.1016/j.isci.2022.105263. eCollection 2022 Oct 21.

Authors

Ermanno Florio¹, Marcello Serra², Robert G Lewis¹, Enikö Kramár³, Michael Freidberg⁴, Marcello Wood³, Micaela Morelli², Emiliana Borrelli¹

Affiliations

¹ Department of Microbiology & Molecular Genetics, INSERM U1233, Center for Epigenetics and Metabolism, 308 Sprague Hall, University of California, Irvine, Irvine, CA 92697, USA.
² Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato (CA), Italy.
³ Department of Neurobiology and Behavior, University of California, Irvine, 200 Qureshey Research Lab., Irvine, CA 92697, USA.
⁴ Department of Chemistry, University of California, Irvine, 1102 Natural Sciences II, Irvine, CA 92697, USA.

Abstract

Degeneration of dopaminergic neurons leads to Parkinson's disease (PD), characterized by reduced levels of striatal dopamine (DA) and impaired voluntary movements. DA replacement is achieved by levodopa treatment which in long-term causes involuntary movements or dyskinesia. Dyskinesia is linked to the pulsatile activation of D1 receptors of the striatal medium spiny neurons (MSNs) forming the direct output pathway (dMSNs). The contribution of DA stimulation of D2R in MSNs of the indirect pathway (iMSNs) is less clear. Using the 6-hydroxydopamine model of PD, here we show that loss of DA-mediated inhibition of these neurons intensifies levodopa-induced dyskinesia (LID) leading to reprogramming of striatal gene expression. We propose that the motor impairments characteristic of PD and of its therapy are critically dependent on D2R-mediated iMSNs activity. D2R signaling not only filters inputs to the striatum but also indirectly regulates dMSNs mediated responses.

Keywords: Behavioral neuroscience; Biological sciences; Neuroscience; Transcriptomics.