The adhesion-GPCR BAI3 and its signaling pathway in schizophrenia: from mice models to patients. – CERBAIS

Schizophrenia is a multifactorial disease with a strong genetic component that is characterized by positive symptoms, negative symptoms and cognitive impairment. It is currently hypothesized that schizophrenia is a neurodevelopmental disorder that affects neuronal dendritogenesis and synaptogenesis. The Brain Angiogenesis Inhibitor family of receptors is a new family of seven-transmembrane receptors whose role in the brain is still poorly described. Several studies have shown the association of polymorphisms or copy number variations in the gene coding for BAI3 with schizophrenia. The characteristics of these receptors and data obtained by the coordinator’s team suggest an important role for BAI receptors in the formation of neuronal networks. In particular, they might coordinate the development of neuronal architecture with synatogenesis during brain development. The proposed project presents a multidisciplinary approach that will bridge basic research with translational research by providing a better understanding of the role of the BAI3 signaling pathway during brain development and of its direct involvement in the symptoms of schizophrenia. The BAI3 receptor is expressed in diverse brain regions including in cerebellar Purkinje cells. Because increasing evidence implicate cerebellar deficits in schizophrenia, especially in patients with high scores of neurological soft signs and stronger cognitive dysfunction, and because of the well-described cellular, physiological and behavioral characteristics of the olivo-cerebellar network, we will focus on the role of BAI3 in Purkinje cell development for our studies of BAI3 signaling and function. First, we will generate genetically modified mouse models with deficits of BAI3 signaling specifically in Purkinje cells and characterize the induced deficits in neuronal network organization at the morphological level, at the physiological level in vitro and in vivo, and at the level of behavior using a neurophenotyping strategy. This study will thus provide a description of the morphological and physiological correlates of behaviors relevant to schizophrenia and identify the symptoms that are due to cerebellar deficits. Second, we will combine genetic tagging in mice, biochemistry and mass spectrometry to identify the synaptic partners of the BAI3 receptor in neurons in vivo, and use a knockdown approach in vivo to validate the role of these candidates in the formation and function of neuronal networks. Finally, we will combine genetic association studies in patients with schizophrenia and functional studies of identified polymorphisms in cultured neurons to provide direct evidence of the role of the BAI3 signaling pathway in schizophrenia. This study will help us identify patients with relevant polymorphisms. We will then be able to transdifferentiate cells from these selected patients into “neurons” so as to confirm the effects of deficits in the BAI3 pathway on neuronal development and more importantly to test whether these deficits can be rescued by genetic modifications. Overall, this project takes advantage of the complementarities of the three partners not only to provide a comprehensive study of the role of a new signaling pathway in schizophrenia, but also new animal models for this disease and functional confirmation of genetic association studies using cellular models established directly from patients. Thus, our study will provide a better understanding of the etiology of schizophrenia, open new avenues of research and provide new potential therapeutic targets for this disease.