Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease.
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.
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Kaoru
K
Yamamoto
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Zen-Ichi
ZI
Tanei
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Tadafumi
T
Hashimoto
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Tomoko
T
Wakabayashi
Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Hiroyuki
H
Okuno
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Yasushi
Y
Naka
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Ofer
O
Yizhar
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Lief E
LE
Fenno
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Masashi
M
Fukayama
Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Haruhiko
H
Bito
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA.
John R
JR
Cirrito
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA.
David M
DM
Holtzman
Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Karl
K
Deisseroth
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: iwatsubo@m.u-tokyo.ac.jp.
Takeshi
T
Iwatsubo
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D055355:Opsins / Q000378:metabolism; D062308:Optogenetics / Q000379:methods*; D019580:Perforant Pathway / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
D016229:Amyloid beta-Peptides; D055355:Opsins