Synapse loss is a key feature of many neurodegenerative diseases involving cognitive deficits, and is also the strongest correlate of cognitive decline in Alzheimer’s disease (AD). In addition, the integrity of dendritic spines, the post-synaptic sites of excitatory synapses, have been shown to play a key role in cognitive resilience against AD. Given the critical role of synaptic loss in cognitive decline, we hypothesized that synaptic compensation and repair play a vital role in counteracting synapse loss and as a consequence, in delaying the onset of cognitive deficits. The aim of our study is to artificially induce spine loss in order to study the emergence of compensatory mechanisms over time using longitudinal imaging. To this end, we use 2-photon microscopy to image dendritic spines in an in-vitro model system: rat organotypic hippocampal slice cultures. To induce spine loss, we promote the degradation of drebrin, a post-synaptic F-actin binding protein that is abundant in spines, using the degradation-tag (dTAG) system. By imaging the same dendrite over time, we visualise structural changes in dendritic spines in both the spine loss phase and the following compensation phase. In our preliminary data, we show the optimization of this dTAG system to induce spine loss, and its ability to promote the emergence of synaptic compensation over days (e.g. the enlargement of surviving spines and regeneration of new spines). Following this, we plan to look into the transcriptional landscape at relevant time points to elucidate the mechanisms of spine compensation.