Mayford M, Bach M E, Huang Y Y, Wang L, Hawkins R D, Kandel E R
Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, and Howard Hughes Medical Institute, 722 West 168 Street, New York, NY 10032, USA.
Science. 1996 Dec 6;274(5293):1678-83. doi: 10.1126/science.274.5293.1678.
One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of calcium-calmodulin-dependent kinase II (CaMKII) resulted in a loss of hippocampal long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit memory task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit memory storage, in a manner that is independent of its potential role in development.
利用基因改造小鼠研究认知功能的主要局限之一是缺乏对基因功能的区域和时间控制。为克服这些局限，将前脑特异性启动子与四环素反式激活系统相结合，以实现对转基因表达的区域和时间控制。表达一种激活的、不依赖钙的钙调蛋白依赖性激酶II（CaMKII）会导致在10赫兹刺激下海马长时程增强效应丧失以及空间记忆缺陷，空间记忆是一种外显记忆形式。转基因表达的抑制可逆转生理和记忆缺陷。当转基因在杏仁核外侧和纹状体而非其他前脑结构中高水平表达时，恐惧条件反射（一种内隐记忆任务）出现缺陷，该缺陷同样是可逆的。因此，CaMKII信号通路对于外显和内隐记忆存储均至关重要，其方式独立于其在发育中的潜在作用。
