P.2.005 - Knock-down of G protein-coupled receptor 88 in the striatum reduces psychiatric symptoms in a rat non-motor model of Parkinson’s disease

Abstract

Although Parkinson's disease (PD) is commonly defined as a progressive motor disorder, it entails many psychiatric non-motor symptoms (NMS) such as depression and cognitive alterations that are irresponsive to L-DOPA treatment and are thus in need of new and more specific targets for their treatment. This underpins interest in Gpr88, a brain-specific orphan G-protein coupled receptor whose expression in the striatal medium spiny neurons is modulated by L-DOPA as well as 6-hydroxydopamine (6OHDA) lesions [1]. Knock-down (KD) of Gpr88 in the ventral striatum (STR) normalizes motor and cognitive alterations in a rat model of psychosis [2], so in this study, we evaluated the impact of Gpr88-KD on depressed mood, sensorimotor gating and social recognition in a model of psychiatric NMS of PD. Partial lesions reproducing several psychiatric symptoms of PD were induced by bilateral stereotaxic injections of 6OHDA (12µg/hemisphere), or control saline, in the dorsolateral STR of rats. Then, Gpr88 was knocked-down using a lentiviral vector co-expressing the emerald Green Fluorescent Protein (emGFP) marker and either a specific (miR-Gpr88) or control (miR-neg) microRNA. These vectors were bilaterally injected into either the ventral (v), dorsomedial (dm), or dorsolateral (dl) STR (2 or 6µl/hemisphere, in the ventral or dorsal regions respectively). The rats were then tested for: depression with the forced swim test (FST); sensorimotor filtering with the Prepulse Inhibition test (PPI, prepulses ranging from 70-80dB and pulse = 110dB); and social recognition with the social novelty discrimination (SND) test, which measures discrimination of a novel from a familiar juvenile rat (score ≥ 3 in controls). The efficacy of the 6-OHDA lesion was quantified by the loss of Tyrosine Hydroxylase (TH) immunofluorescence, and the lentiviral transduction extent and location was validated by emGFP detection. Statistical analyses were performed using one-way ANOVA followed by Bonferroni corrections. Results are expressed as means ± SEM. The 6-OHDA lesion was limited to the dlSTR where it induced a significant loss of TH immunoreactivity (-57.10% ± 4.23, p Taken together, these results indicate that striatal Gpr88 KD moderates striatal dopamine depletion related alterations in mood, sensory motor gating and social discrimination in a model of NMS of PD. This study thus highlights the relevance of GPR88 as a potential target for the control of the psychiatric symptoms of PD, and possibly of other neuropsychiatric diseases.