Yamamoto Kaoru, Tanei Zen-Ichi, Hashimoto Tadafumi, Wakabayashi Tomoko, Okuno Hiroyuki, Naka Yasushi, Yizhar Ofer, Fenno Lief E, Fukayama Masashi, Bito Haruhiko, Cirrito John R, Holtzman David M, Deisseroth Karl, Iwatsubo Takeshi
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
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.
Cell Rep. 2015 May 12;11(6):859-865. doi: 10.1016/j.celrep.2015.04.017. Epub 2015 Apr 30.
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.
体内实验证据表明，急性神经元激活会增加突触前末端的Aβ释放，而慢性突触激活对Aβ病理的长期影响仍不清楚。为了解决这个问题，我们采用光遗传学技术，将稳定的阶跃函数视蛋白（一种经过工程改造以引发持久神经元过度兴奋的通道视紫红质）转导到APP转基因小鼠的海马穿通通路中。体内微透析显示，急性光激活后，海马间质液中Aβ42水平立即升高约24%。与对侧相比，五个月的慢性光遗传学刺激使受刺激侧穿通通路投射区域（即齿状回外分子层）的Aβ负担增加了约2.5倍。在慢性刺激过程中观察到癫痫发作，这可能部分导致了Aβ病理。这些发现表明特定神经元回路的功能异常与Aβ病理和阿尔茨海默病有关。
