ABSTRACT Synapses are important structures connecting neurons and enabling fast signal transmission, providing the building block of brain function. Advancements in sophisticated microscopy and electrophysiology technologies have revealed significant heterogeneity among synapses, with the caveat that most of these studies have been done in rodent model systems, while little is known about human synapse heterogeneity and molecular composition. Synaptic dysfunction, often referred to as synaptopathy, encompasses numerous cellular, molecular and structural changes, which ultimately lead to progressive loss of synapses, a disease-associate phenotype originally proposed for Alzheimer’s disease, but since then also proposed as an early sign of disease manifestation in other neurodegenerative diseases, including FTD and ALS. The latter has been demonstrated in mouse models of familial FTD, but also in postmortem tissue of ALS/FTD patients, including those carrying the C9orf72 mutation. More recent studies suggest that synapse loss might be preceded by changes in the protein and RNA content of the synaptic structure itself, both pre-and postsynaptic. Meanwhile, C9orf72 protein has been shown to be localized to the postsynaptic and presynaptic compartment, supporting C9orf72’s function in vesicle trafficking and its activity as a Rab GTPase guanine exchange factor (GEF). Limited studies suggest that the C9orf7 mutation induces disease-associated changes of the synaptome, but a comprehensive and unbiased profiling of protein and RNA signatures at the diseased human cortical neuronal synapse is still missing. At the same time, an aberrant synapse proteome and/or transcriptome have yet to be correlated with aberrant microglia function, including synaptic pruning, and it is still poorly understood whether these pathological events are initiated by microglia or by synaptic changes. The graduate student assigned to this project, Ashton Spillman, will perform a comprehensive assessment on if and how signals from cortical neuronal synapses to microglia lead to pathological synapse elimination in C9orf72-FTD using postmortem patient autopsy tissue and iPSC neuron and microglia culture models in association with multi-omics and functional analyses. We hypothesize that the C9orf72 repeat expansion-induced aberrant synaptome contributes to the activation of microglia and aberrant microglia-associated synaptic pruning in C9orf72 FTD. These studies are critically important for our understanding of what role synapse elimination plays and how it could lead to novel therapeutic target identification, either directed at the synaptic proteome itself and/or the associated immune signaling.