Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease

Abstract

The immediate-early gene Arc mediates synaptic plasticity and long-term memory formation. Whether Arc is dysregulated by amyloid-beta or in Alzheimer's disease is controversial. Here, a study used a reporter mouse line expressing destabilized fluorescent protein Venus under the control of the Arc promoter to show that Arc induction pattern, brain regional difference and precise location of active neurons with respect to senile plaque are major determinants of differential Arc response in a mouse model of Alzheimer's disease. Experience-induced expression of immediate-early gene Arc (also known as Arg3.1) is known to be important for consolidation of memory. Using in vivo longitudinal multiphoton imaging, we found orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicted the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer's disease, this association was markedly disrupted in the cortex, specifically near senile plaques. Neurons in the vicinity of plaques were less likely to respond, but, paradoxically, there were stronger responses in those few neurons around plaques that did respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to and physiological consolidation of behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration.