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

Kaoru Yamamoto, Zen ichi Tanei, Tadafumi Hashimoto, Tomoko Wakabayashi, Hiroyuki Okuno, Yasushi Naka, Ofer Yizhar, Lief E. Fenno, Masashi Fukayama, Haruhiko Bito, John R. Cirrito, David M. Holtzman, Karl Deisseroth, Takeshi Iwatsubo

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Abstract

Invivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects ofchronic synaptic activation on Aβ 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. Invivo microdialysis revealed a ~24% increase in the hippocampal interstitial fluid Aβ42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Aβ burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ~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 Aβ pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Aβ pathology and Alzheimer disease.

Original languageEnglish
Pages (from-to)859-865
Number of pages7
JournalCell Reports
Volume11
Issue number6
DOIs
StatePublished - May 12 2015

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    Yamamoto, K., Tanei, Z. I., Hashimoto, T., Wakabayashi, T., Okuno, H., Naka, Y., Yizhar, O., Fenno, L. E., Fukayama, M., Bito, H., Cirrito, J. R., Holtzman, D. M., Deisseroth, K., & Iwatsubo, T. (2015). Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease. Cell Reports, 11(6), 859-865. https://doi.org/10.1016/j.celrep.2015.04.017