Understanding the role of microglia in neurodevelopmental disorders

Objective

Neurodevelopmental disorders like autism (ASD) and Fragile X syndrome (FXS) are associated with changes in microglia function and synaptic pruning. No approved or effective therapies exist for FXS/ASD. Novel therapies are needed that target microglia, distinct from conventional drugs targeting neurons. Research on synaptic pruning mediated by microglia is scarce, and the role of microglia in FXS/ASD has been overlooked. Previous studies, including my own work and studies from the host laboratory, however, advanced approaches for analysis of microglia-synapse interactions and demonstrated that the abnormal pruning may be associated with the Integrated Stress Response (ISR) pathway since the elevated phosphorylation of eIF2α is linked to neuroinflammatory disorders characterized by excessive synapse loss. Thus, impaired microglial eIF2α phosphorylation may decrease synaptic pruning, highlighting eIF2α as an attractive target for restoring synaptic pruning in FXS/ASD. My project aims to uncover microglia's contribution to FXS/ASD pathophysiology. First, I will address how the FXS/ASD state affects synaptic pruning by microglia, microglial morphology, and function. Second, I will explore the role of microglia and FAM69, a novel kinase mediating eIF2α phosphorylation, in impaired synaptic pruning at the molecular and cellular levels. Genetically engineered mice and human brain organoids will facilitate visualization and targeting of microglia-synapse interaction. To assess changes in synaptic pruning, I will use viral vector-assisted silencing and overexpression of microglial FAM69, validating their impact on synaptic pruning by vital two-photon microscopy. Finally, I will evaluate whether these interventions can alleviate autism-like behavior. With this integrative approach, I aim to uncover novel molecular pathways mediating the synaptic pruning by microglia and to identify new targets for the treatment of FXS/ASD.