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
Affiliations
Kaoru Yamamoto
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Zen-ichi Tanei
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Tadafumi Hashimoto
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Tomoko Wakabayashi
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Hiroyuki Okuno
Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Yasushi Naka
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Ofer Yizhar
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Lief E. Fenno
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Masashi Fukayama
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Haruhiko Bito
Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
John R. Cirrito
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110, USA
David M. Holtzman
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110, USA
Karl Deisseroth
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA
Takeshi Iwatsubo
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
In vivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects of chronic 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. In vivo 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.
