A Drosophila screen of schizophrenia-related genes highlights the requirement of neural and glial matrix metalloproteinases for neuronal remodeling

Schizophrenia (SCZ) is a multifactorial neuropsychiatric disorder of complex and mostly unknown etiology, affected by genetic, developmental and environmental factors. Neuroanatomical abnormalities, such as loss of grey matter, are apparent prior to the onset of symptoms, suggesting neurodevelopmental origin. Indeed, it has been hypothesized, and recently experimentally supported, that SCZ is associated with dysregulation of developmental synaptic pruning. Here, we explore the molecular link between SCZ-associated genes and developmental neuronal remodeling, focusing on the Drosophila mushroom body (MB), which undergoes stereotypic remodeling during metamorphosis. We conducted a loss-of-function screen in which we knocked down Drosophila homologs of human genes that genomic studies have associated with SCZ. Out of our ‘positive hits’, we focused on matrix metalloproteinases (MMPs), mostly known for their role in remodeling of the extracellular matrix. We found that both Mmp1 and Mmp2, which are closely-related to mammalian MMPs, are required in neurons and in glia for the pruning of MB axons. Our combinatorial loss-of-function experiments suggest that Mmp2 secretion from glia is the most important promoter of axon pruning. Our results shed new light on potential molecular players underlying neurodevelopmental defects in SCZ and highlight the advantage of genetically tractable model organisms in the study of human neurodevelopmental disorders.