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

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 AD mouse model expressing human amyloid protein precursor with the Swedish and Indiana mutations (hAPP mutations) exhibit aberrant c-Fos expression and altered synaptic structures at a pre-amyloid plaque stage. However, it is unclear whether aberrant c-Fos expression and synaptic pathology vary across the broader visual network and to what extent c-Fos abnormality in the cortex is inherited through functional connectivity. Using both sexes of 4-6-month AD model mice with hAPP mutations (J20[PDGF-APPSw, Ind]), we found that cortical regions of the visual network show aberrant c-Fos expression and impaired experience-dependent modulation while subcortical regions do not. Interestingly, the average network-wide functional connectivity strength of a brain region in wild type (WT) mice significantly predicts its aberrant c-Fos expression, which in turn correlates with impaired experience-dependent modulation in the AD model. Using in vivo two-photon and ex vivo imaging of presynaptic termini, we observed a subtle yet selective weakening of excitatory cortical synapses in the visual cortex. Intriguingly, the change in the size distribution of cortical boutons in the AD model is downscaled relative to those in WT mice, suggesting that synaptic weakening may reflect an adaptation to aberrant activity. Our observations suggest that cellular and synaptic abnormalities in the AD model represent a maladaptive transformation of the baseline physiological state seen in WT conditions rather than entirely novel and unrelated manifestations.