Sorbonne Universités / China Scholarship Council program Thesis proposal (maximum 2 pages) (à transmettre à l’Ecole doctorale) Title: Translational studies on the brain orphan receptor Gpr88, a new therapeutic target for neuropsychiatric diseases. Scientific domain: Neurosciences Key words: Neuropsychiatric diseases, orphan receptor, animal models, gene transfer, lentiviral vectors, microRNA, CRISPR-Cas9 system, behavior Joint supervision: Yes ☐ No ☒ Joint PhD (cotutelle): Yes ☐ No ☒ Thesis supervisor(s): Rolando Meloni Institution of the thesis supervisor(s): Institut du Cerveau et de la Moelle épinière (ICM) Email address of the thesis supervisor(s): [email protected] Doctoral school: ED3C Research laboratory: Biotechnology and Biotherapy laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM) Address of the laboratory: CHU Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75013 Paris, France Website of the laboratory: http://icm-institute.org Name of the laboratory director: Alexis Brice Email of the laboratory director: [email protected] Telephone number of the laboratory director: 01.57.27.46.68 Subject description (2 pages max.): Gpr88 is a G protein-coupled orphan receptor, which is expressed almost exclusively in the striatum where it appears to interact with dopamine and glutamate neurotransmission. We have previously found by psychiatric genetic studies that Gpr88 is associated to bipolar disorder and schizophrenia. Our results and several other studies showing that Gpr88 KO causes motor and/or cognitive deficits suggest that Gpr88 represent a new therapeutic target for neuropsychiatric diseases. To address the role of Gpr88 in mental diseases, we have generated an animal model of schizophrenia by treating newborn rats with phencyclidine (PCP). This treatment induces in the adult animal behavioral alterations reproducing the positive, negative and cognitive symptoms that characterize schizophrenia. Thereafter, we have knocked-down (KD) Gpr88 in the Nucleus Accumbens of the adult rats by lentiviral-mediated microRNA (miR) transfer. The Nucleus Accumbens, localized in the ventral part of the striatum, plays a fundamental role in the gating of the information flow, a function that is deeply altered in the course of schizophrenia. We found that the local Gpr88 KD significantly reduces the motor hypersensitivity to psychotomimetic drugs and completely normalizes the deficits in a social cognition task that are provoked by the PCP treatment. These results are all the more remarkable since the KD of the dopamine receptor D2, which is the main target of neuroleptic drugs, does not have any effect on the social cognition deficit. Based on these findings, we will continue to further characterize Gpr88 as a novel target for the treatment of cognitive deficits that are refractory to the currently used drugs and that characterize not only schizophrenia but also other neuropsychiatric diseases such as depression or Parkinson’s disease. In this perspective, we will develop animal models of neuropsychiatric diseases and then evaluate the impact of the KD of Gpr88 in the dorsal or ventral striatum at the molecular, cellular and behavioral levels in order to establish the role of Gpr88 and identify the genetic and signaling networks in which Gpr88 operates. The animal models will be developed by chronic or sub-chronic pharmacological treatments with psychotropic drugs such as, for example, PCP or amphetamine (schizophrenia, bipolar disorder, depression…), environmental stressors such as social isolation, perinatal nutritional imbalance (depression), sleep deprivation (bipolar disorder), neurotoxins such as 6-hydroxy-dopamine (Parkinson’s disease). Behavioral tests will assess motility, anxiety, depression-like behavior, cognition and social interaction. Molecular and cellular studies will be based on transcriptomic and proteomic approaches for parsing Gpr88 function. For the inactivation of Gpr88 and/or other relevant genes identified as functionally associated to Gpr88 networks in the brain, we will utilize the miR-mediated KD and will develop the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPRassociated to Cas9 system in order to compare the respective efficiency and outcome of these techniques. In conclusion, this project will allow for the characterization, by localized brain gene expression manipulation, and, at the same time, the functional validation of the orphan receptor Gpr88 as a therapeutic target for neuropsychiatric diseases. Moreover, in the long term, this project may generate an important breakthrough for the materialization of the concept of the therapeutic utilization of vector-mediated brain fine gene expression manipulation in mental diseases. Two major publications in the domain of the thesis proposal: 1) Del Zompo M, Deleuze J-F, Chillotti C, Cousin E, Niehaus D, Ebstein RP, Ardau R, Macé S, Warnich L, Mujahed M, Severino G, Dib C, Jordaan E, Murad I, Soubigou S, Koen L, Bannoura I, Rocher C, Laurent C, Derock M, Faucon Biguet N, Mallet J, Meloni R (2014) Association study in three different populations between the GPR88 gene and major psychoses. Molecular Genetics & Genomic Medicine 2:152-159. http://dx.doi.org/10.1002/mgg3.54 2) Ingallinesi M, Le Bouil L, Faucon Biguet N, Do Thi A, Mannoury la Cour C, Millan MJ, Ravassard P, Mallet J, Meloni R (2014) Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats. Mol Psychiatry (in press). http://dx.doi.org/10.1038/mp.2014.92