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 investigate aberrant visual network and brain-wide c-Fos expression and functional connectivity patterns, network responses to light deprivation, and visual system presynaptic deficits of a mouse model of Alzheimer's disease. We found that the mouse model of AD exhibits aberrant c-Fos expression and functional connectivity patterns across multiple brain regions, and functional connectivity between brain regions is a significant predictor for aberrant c-Fos expression. We also show that one week of light deprivation increases c-Fos expression across the brain in nonpathological controls but not the AD model, indicating experience-dependent plasticity deficits in multiple brain regions. Using in vivo and ex vivo imaging of presynaptic termini, we found that aberrant visual cortical c-Fos expression 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 pre-plaque amyloidosis.

Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions.

Neuronal hyperactivity induces memory deficits in Alzheimer's disease. However, how hyperactivity disrupts memory is unclear. Using in vivo synaptic imaging in the mouse visual cortex, we show that structural excitatory-inhibitory synapse imbalance in the apical dendrites favors hyperactivity in early amyloidosis. Consistent with this, natural images elicit neuronal hyperactivity in these mice. Compensatory changes that maintain activity homeostasis disrupt functional connectivity and increase population sparseness such that a small fraction of neurons dominates population activity. These properties reduce the selectivity of neural response to natural images and render visual recognition memory vulnerable to interference. Deprivation of non-specific visual experiences improves the neural representation and behavioral expression of visual familiarity. In contrast, in non-pathological conditions, deprivation of non-specific visual experiences induces disinhibition, increases excitability, and disrupts visual familiarity. We show that disrupted familiarity occurs when the fraction of high-responsive neurons and the persistence of neural representation of a memory-associated stimulus are not constrained.