Affiliations: [a]
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA
| [b]
Department of Neurosurgery, Columbia University Medical Center, New York, NY, USA
Correspondence:
[*]
Correspondence to: Jaichandar Subramanian, Department of Pharmacology and Toxicology, 1251 Wescoe Hall Drive, Malott Hall Room 5060, University of Kansas, Lawrence, KS 66045, USA. Tel.: +1 785 864 3110; E-mail: jaichandar@ku.edu.
Abstract: Background:While Alzheimer’s disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective:We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods:c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4–6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results:Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. Conclusions:Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions.
