Abstract
The limited success of plaque-reducing therapies in Alzheimer's disease suggests that early treatment might be more effective in delaying or reversing memory impairments. Toward this end, it is important to establish the progression of synaptic and circuit changes before onset of plaques or cognitive deficits. Here, we used quantitative, fluorescence-based methods for synapse detection in CA1 pyramidal neurons to investigate the interaction between abnormal circuit activity, measured by Fos-immunoreactivity, and synapse reorganization in mouse models of amyloidosis. Using a genetically encoded, fluorescently labeled synaptic marker in juvenile mice (prior to sexual maturity), we find both synapse gain and loss depending on dendritic location. This progresses to broad synapse loss in aged mice. Elevated hippocampal activity in both CA3 and CA1 was present at weaning and preceded this reorganization. Thus, Aβ overproduction may initiate abnormal activity and subsequent input-specific synapse plasticity. These findings indicate that sustained amyloidosis drives heterogeneous and progressive circuit-wide abnormalities.