Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease

In vivo experimental evidence indicates that acute neuronal activation increases Ab release from presynaptic terminals, whereas long-term effects of chronic synaptic activation on Ab pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. In vivo microdialysis revealed a similar to 24% increase in the hippocampal interstitial fluid A beta 42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Ab burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by similar to 2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Ab pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Ab pathology and Alzheimer disease.