Role of intracellular Ca2+ stores for an impairment of visual processing in a mouse model of Alzheimer's disease.

Besides deficits in memory and cognition, impaired visual processing is common for Alzheimer's disease (AD) patients and mouse models of AD but underlying mechanisms still remain unclear. Using in vivo Ca2+ imaging of the mouse primary visual cortex (V1) we tested whether such impairment is caused by neuronal hyperactivity, an emerging functional hallmark of AD. Profound neuronal hyperactivity was indeed found in V1 of APPSWE/PS1G384A and even of PS1G384A mice, presenting neither with plaque accumulation nor with neuroinflammation. This hyperactivity was accompanied by over-responsiveness to visual stimuli and impaired visual tuning properties of individual neurons, largely caused by insufficient suppression of responses to non-preferred orientation/direction stimuli. Moreover, visual stimulation robustly suppressed the ongoing spontaneous activity in WT but not in APPSWE/PS1G384A mice. Emptying intracellular Ca2+ stores significantly reduced neuronal hyperactivity and the pathological over-responsiveness to visual stimuli, but could not rescue stimulus-induced suppression of spontaneous activity and impaired tuning properties of individual cells. Thus, our data identify the AD-mediated dysfunction of intracellular Ca2+ stores as a main cause of pathologically increased visual responsiveness in APPSWE/PS1G384A mice. At the same time, the impairment of visual tuning and the stimulus-induced suppression of spontaneous activity, identified in this study, are likely caused by different mechanisms as, for example, dysfunction of local interneurons.