Center for Neural Science, New York University, New York, United States.
Elife. 2020 May 5;9:e54781. doi: 10.7554/eLife.54781.
Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation. CIM6P/IGF2R controls the training-induced upregulation of protein synthesis, including increase of Arc, Egr1, and c-Fos proteins, without affecting their mRNA induction. Hippocampal or systemic administration of mannose-6-phosphate, like IGF2, significantly enhances memory retention and persistence in a CIM6P/IGF2R-dependent manner. Thus, hippocampal CIM6P/IGF2R plays a critical role in memory consolidation by controlling the rate of training-regulated protein metabolism and is also a target mechanism for memory enhancement.
阳离子非依赖型甘露糖-6-磷酸受体，也称为胰岛素样生长因子 II 受体（CIM6P/IGF2R），在生长和发育中发挥重要作用，但在成熟的神经系统中也广泛表达，特别是在海马体中，其功能尚不清楚。它的主要配体之一 IGF2 对于长期记忆的形成和增强至关重要。通过在大鼠中抑制 CIM6P/IGF2R 和在小鼠中神经元特异性敲低，我们发现海马体中的 CIM6P/IGF2R 对于海马体依赖性记忆巩固是必需的，但对于学习、记忆检索和再巩固是可有可无的。CIM6P/IGF2R 控制训练诱导的蛋白质合成上调，包括 Arc、Egr1 和 c-Fos 蛋白的增加，而不影响它们的 mRNA 诱导。像 IGF2 一样，海马体或全身给予甘露糖-6-磷酸以 CIM6P/IGF2R 依赖的方式显著增强记忆保留和持久性。因此，海马体中的 CIM6P/IGF2R 通过控制训练调节的蛋白质代谢率在记忆巩固中发挥关键作用，也是增强记忆的目标机制。
