Abstract
Schizophrenia is a multifactorial neuropsychiatric disorder of complex and mostly unknown etiology, affected by genetic, developmental, and environmental factors. Neuroanatomical abnormalities, such as loss of gray matter, are apparent before the onset of symptoms, suggesting a neurodevelopmental origin. Indeed, it has been hypothesized, and recently experimentally supported, that schizophrenia is associated with dysregulation of developmental synaptic pruning. Here, we explore the molecular link between schizophrenia-associated genes and developmental neuronal remodeling. We focused on the Drosophila mushroom body, which undergoes stereotypic remodeling during metamorphosis. We conducted a loss-of-function screen in either glia or neurons of Drosophila homologs of human genes that are associated with schizophrenia based on genomic studies. Out of our "positive hits," we focused on matrix metalloproteinases. Our combinatorial loss-of-function experiments suggest that Drosophila matrix metalloproteinases are required both in neurons and in glia for the pruning of mushroom body axons. Our results shed new light on potential molecular players underlying neurodevelopmental defects in schizophrenia and highlight the advantage of genetically tractable model organisms in the study of human neurodevelopmental disorders.
