During early stages of Alzheimer’s disease (AD) gradual accumulation and aggregation of Aβ oligomers (AβO) occurs prior to cognitive decline. This preclinical stage of AD is further characterized by synaptic dysfunction and network hyperexcitability. We recently discovered that 24-hour treatment of AβO​​​​​ to hippocampal slices impairs release at GABAergic synapses, most prominently at dendritic inhibitory synapses. This suggests that inhibitory synapses are particularly vulnerable to AβO toxicity.We currently use advanced imaging approaches in vitro to further investigate the mechanisms that underlie the differential impact of AβO exposure on glutamatergic and GABAergic synapses.We optically probed synaptic release at excitatory and inhibitory synapses, using live antibody uptake assay of syt1 antibody. We observed that exposure to low levels of AβO specifically impaired synaptic vesicle turnover at inhibitory presynaptic boutons, while turnover at excitatory boutons remained unaffected. The impaired GABA release at inhibitory boutons resulted in network hyperactivity in these neuronal cultures. In addition, we observed that AβO exposure resulted in a 30-40% reduction of endogenous Gephyrin puncta density, while PSD95 puncta density was reduced by only ~10%.Our data indicates that inhibitory synapses are particularly vulnerable to AβO toxicity and suggest that early network defects might primarily result from the preferential effect of AβO on inhibitory synapses during early stages of AD. We hypothesize that the differential vulnerability to AβO could result from intrinsic differences in the nanoscale architecture of synapses. We plan to investigate our hypothesis using CRISPR-Cas9 based endogenous labeling of target proteins combined with super-resolution microscopy.