The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic loss in AD, how neurons compensate for this loss and whether this provides cognitive benefits remain almost completely unexplored. In this review, we describe two potential compensatory mechanisms implemented following synaptic loss: the enlargement of the surviving neighboring synapses and the regeneration of synapses. Because dendritic spines, the postsynaptic site of excitatory synapses, are easily visualized using light microscopy, we focus on a range of microscopy approaches to monitor synaptic loss and compensation. Here, we stress the importance of longitudinal dendritic spine imaging, as opposed to fixed-tissue imaging, to gain insights into the temporal dynamics of dendritic spine compensation. We believe that understanding the molecular mechanisms behind these and other forms of synaptic compensation and regeneration will be critical for the development of therapeutics aiming at delaying the onset of cognitive deficits in AD.
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