Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in amyloidosis

While Alzheimer’s disease (AD) has been extensively studied with a focus on cognitive networks, sensory network dysfunction has received comparatively less attention despite compelling evidence of its significance in both Alzheimer’s disease patients and mouse models. We recently found that neurons in the primary visual cortex of an amyloid mouse model exhibit an imbalance of postsynaptic structures favoring neuronal hyperactivity alongside increased c-Fos expression, which regulates plasticity and memory. Here, we map c-Fos expression in the visual network and across the brain in a mouse model of Alzheimer’s disease. We found that the mouse model of AD exhibits aberrant c-Fos expression in multiple brain regions, and functional connectivity between brain regions is a significant predictor for aberrant cFos expression. We also show that depriving visual experience increases c-Fos expression in nonpathological controls across the brain but not the AD model, indicating experience-dependent plasticity deficits in multiple brain regions. Using in vivo and ex vivo imaging of presynaptic terminals, we found that aberrant cFos is associated with selective loss of excitatory cortical but not inhibitory or subcortical synapses. Our findings reveal novel structural and functional connectivity deficits in the visual network in amyloid pathology.