Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Neuromolecular Med. 2013 Mar;15(1):74-81. doi: 10.1007/s12017-012-8196-8. Epub 2012 Aug 19.
In the central nervous system, two calpain isoforms are highly expressed: calpain1 and calpain2. Here, we show for the first time that activation of the calpain isoform, calpain2, is a necessary event in hippocampal synaptic plasticity and in learning and memory. We developed a fluorescence resonance energy transfer-based animal model to monitor in vivo calpain activation in single cells and in real time. Additionally, utilizing a novel rabies virus glycoprotein-chimeric peptide, which enabled the transvascular delivery of small interfering RNA to the brain against calpain2, we down-regulated the calpain2 isoform in vivo. Calpain2 gene silencing eliminated long-term potentiation and impaired learning and memory. Our results not only identify the calpain2 isoform as a critical mediator in learning and memory but also highlight an innovative, highly efficient calpain2-targeting peptide capable of isoform-specific gene silencing in the brain. We anticipate these innovative technologies and our better understanding of the calpain machinery, particularly of the calpain2 isoform, will have substantial influence on future translational studies, attracting considerable interest in the use of calpain models and calpain-specific inhibitors in the development of therapeutics.
在中枢神经系统中，两种钙蛋白酶同工酶高度表达：钙蛋白酶 1 和钙蛋白酶 2。在这里，我们首次表明钙蛋白酶同工酶钙蛋白酶 2 的激活是海马突触可塑性以及学习和记忆所必需的事件。我们开发了一种基于荧光共振能量转移的动物模型，以在单个细胞中实时监测体内钙蛋白酶的激活。此外，利用一种新型狂犬病毒糖蛋白嵌合肽，它能够将针对钙蛋白酶 2 的小干扰 RNA 经血管递送至大脑，我们在体内下调钙蛋白酶 2 同工酶。钙蛋白酶 2 基因沉默消除了长时程增强作用，并损害了学习和记忆。我们的研究结果不仅确定了钙蛋白酶 2 同工酶作为学习和记忆的关键介质，而且还突出了一种创新的、高效的钙蛋白酶 2 靶向肽，该肽能够在大脑中进行同工酶特异性基因沉默。我们预计这些创新技术以及我们对钙蛋白酶机制的更好理解，特别是对钙蛋白酶 2 同工酶的理解，将对未来的转化研究产生重大影响，引起人们对钙蛋白酶模型和钙蛋白酶特异性抑制剂在治疗药物开发中的应用的极大兴趣。
