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发现长期记忆的分子机制
诸平
据巴塞尔大学(University of Basel)2020年11月30日提供的消息,该大学的研究人员发现了一种分子机制,在完整的长期记忆中起着核心作用。该机制还与老年生理记忆丧失有关。
巴塞尔大学的研究人员发现了一种分子机制,在完整的长期记忆中起着核心作用。该机制还与老年生理记忆丧失有关。
从蠕虫(worms)到人类,许多生命形式都有不同的记忆功能,例如短期和长期记忆。有趣的是,在细胞和分子水平上,许多功能从生命形式到生命形式都几乎相同。检测涉及记忆过程的分子对于基础研究和临床研究都非常重要,因为它可以为开发用于记忆障碍的药物指明道路。
通过研究特定蠕虫(roundworms,Caenorhabditis elegans),巴塞尔大学分子与认知神经科学跨学科研究平台(Transfaculty Research Platform for Molecular and Cognitive Neurosciences)的科学家现在发现了长期记忆的分子机制,该机制也与老年记忆丧失有关。他们在《当代生物学》(Current Biology)杂志上报告了他们的发现——Bank G. Fenyves, Andreas Arnold, Vaibhav G. Gharat, Carmen Haab, Kiril Tishinov, Fabian Peter, Dominique de Quervain, Andreas Papassotiropoulos, Attila Stetak. Dual Role of an mps-2/KCNE-Dependent Pathway in Long-Term Memory and Age-Dependent Memory Decline. Current Biology, 2020; DOI: 10.1016/j.cub.2020.10.069。
由Attila Stetak博士,Andreas Papassotiropoulos教授和Dominique de Quervain教授领导的研究小组使用感觉刺激首先检查了缺少某种基因mps-2的转基因特定蠕虫的学习和记忆能力。该基因包含神经细胞膜中部分电压依赖性离子通道的蓝图,并被怀疑在记忆功能中起作用。
人们发现,改良特定的蠕虫与未经改良的标本具有同样好的短期记忆。但是,随着实验时间的延长,研究人员发现转基因特定的蠕虫无法保留所学知识。没有mps-2,他们的长期记忆减少。
与年龄有关的记忆丧失
与人类一样,在特定的蠕虫中,随着年龄的增长,记忆力会下降。但是,该过程的分子基础尚不清楚。在进一步的实验中,研究人员能够证明具有mps-2基因的未经修饰的特定蠕虫在老年时表现出MPS-2蛋白(该基因的产物)的强烈减少。这与降低的内存性能有关。
缺乏MPS-2蛋白被证明不是一个被动的过程,而是一个主动调节的过程。研究小组能够鉴定出另一种蛋白质NHR-66,该蛋白质负责调节这种缺陷。NHR-66积极抑制mps-2基因的读取,从而抑制老年MPS-2蛋白的产生。如果在较老的蠕虫中人为地诱导了MPS-2蛋白水平或关闭了它们的NHR-66,则它们具有与较年轻的蠕虫类似的良好记忆。因此,MPS-2和NHR-66这两种分子都是可以减轻与年龄有关的记忆丧失的药物的有趣靶标。在进一步的研究中,研究人员希望根据他们的发现来检查治疗方案。更多信息请注意浏览原文或者相关报道。
• MPS-2/KCNE controls long-term associative memory
• MPS-2 is in complex and acts through KVS-3 and KVS-4 voltage-gated K+ channels
• Age-dependent memory decline is linked to MPS-2 expression levels
• NHR-66 actively represses MPS-2 expression, controlling age-dependent memory decline
Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (Kv) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating Kv channels; however, their possible role in the regulation of memory and age-dependent memory decline are unknown. Here, we show that, in Caenorhabditis elegans (C. elegans), mps-2 is the sole member of the MiRP family that controls exclusively long-term associative memory (LTAM) in AVA neuron. In addition, we demonstrate that mps-2 also plays a critical role in age-dependent memory decline. In young adult worms, mps-2 is transcriptionally upregulated by CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) during LTAM, although the mps-2 baseline expression is CREB independent and instead, during aging, relies on nhr-66, which acts as an age-dependent repressor. Deletion of nhr-66 or its binding element in the mps-2 promoter prevents age-dependent transcriptional repression of mps-2 and memory decline. Finally, MPS-2 acts through the modulation of the Kv2.1/KVS-3 and Kv2.2/KVS-4 heteromeric potassium channels. Altogether, we describe a conserved MPS-2/KVS-3/KVS-4 pathway essential for LTAM and also for a programmed control of physiological age-dependent memory decline.
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