Molecular and Genetic Dissection of Neural Circuit Remodeling Defects in a Fragile X Syndrome Disease Model

Abstract

Brain circuit refinement is characterized by early hyper-connectivity followed by regressive loss of neurons and synapses during critical period remodeling. This pruning is impaired in the common intellectual disability and autism spectrum disorder Fragile X syndrome (FXS), which is caused by loss of Fragile X Mental Retardation Protein (FMRP). The aim of this dissertation was to identify molecular and cellular mechanisms of neuron and synapse elimination during this brain circuit remodeling using the genetically-tractable Drosophila FXS disease model. First, mining results from a brain proteomics screen in this model, I identified elevated expression of the Shrub protein, an essential core component of an endosomal sorting complex required for transport (ESCRT). I showed that a membrane trafficking error is a major contributor of synaptic remodeling defects in the central brain. Second, based on earlier work from the Broadie Lab, I discovered that neuron-to-glia intercellular communication drives the phagocytic removal of neurons during circuit remodeling in the central brain. I showed neuronal FMRP controls glial insulin receptor (InR) activation for Draper-dependent glial phagocytosis of Shrub-fragmented neurons, with 1) InR activation, 2) glial Draper expression or 3) genetically correcting Shrub levels in the FXS model all restoring neuronal clearance. This thesis work has identified numerous new mechanistic insights into FXS brain circuit remodeling defects, suggesting avenues for future therapeutic intervention.