Laboratory of Neuroepigenetics, University of Zurich/Swiss Federal Institute of Technology, Brain Research Institute, Neuroscience Center Zürich, Zurich CH-8057, Switzerland.
Friedrich Miescher Institute for Biomedical Research, Basel CH-4048, Switzerland.
Nat Commun. 2016 Aug 25;7:12594. doi: 10.1038/ncomms12594.
Memory formation is a complex cognitive function regulated by coordinated synaptic and nuclear processes in neurons. In mammals, it is controlled by multiple molecular activators and suppressors, including the key signalling regulator, protein phosphatase 1 (PP1). Here, we show that memory control by PP1 involves the miR-183/96/182 cluster and its selective regulation during memory formation. Inhibiting nuclear PP1 in the mouse brain, or training on an object recognition task similarly increases miR-183/96/182 expression in the hippocampus. Mimicking this increase by miR-183/96/182 overexpression enhances object memory, while knocking-down endogenous miR-183/96/182 impairs it. This effect involves the modulation of several plasticity-related genes, with HDAC9 identified as an important functional target. Further, PP1 controls miR-183/96/182 in a transcription-independent manner through the processing of their precursors. These findings provide novel evidence for a role of miRNAs in memory formation and suggest the implication of PP1 in miRNAs processing in the adult brain.
记忆形成是一种复杂的认知功能，受神经元中协调的突触和核过程调节。在哺乳动物中，它受多种分子激活剂和抑制剂的控制，包括关键信号调节剂蛋白磷酸酶 1（PP1）。在这里，我们表明，PP1 通过 miR-183/96/182 簇及其在记忆形成过程中的选择性调节来控制记忆。在小鼠大脑中抑制核 PP1，或在物体识别任务中进行训练，同样会增加海马体中 miR-183/96/182 的表达。通过 miR-183/96/182 的过表达模拟这种增加会增强物体记忆，而敲低内源性 miR-183/96/182 则会损害它。这种效应涉及到几个与可塑性相关的基因的调节，其中 HDAC9 被确定为一个重要的功能靶标。此外，PP1 通过其前体的加工以转录非依赖性的方式控制 miR-183/96/182。这些发现为 miRNA 在记忆形成中的作用提供了新的证据，并表明 PP1 在成年大脑中 miRNA 加工中的作用。
