Trans-synaptic Signaling Group, European Neuroscience Institute, 37077 Goettingen, Germany.
German Center for Neurodegenerative Disease, 37075 Goettingen, Germany.
Science. 2019 Jan 4;363(6422). doi: 10.1126/science.aav1483. Epub 2018 Dec 13.
Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.
遗忘很重要。没有遗忘，在不断变化的环境中，后天获得的记忆的相对重要性就会丧失。我们发现突触结合蛋白 3（Syt3）定位于突触后内吞区，并在受到刺激时将 AMPA 受体从突触质膜中内吞。AMPA 受体内化、长时程压抑（LTD）和长时程增强（LTP）的突触强度衰减都需要 Syt3 通过钙感应来实现，而 Syt3 敲除则消除了这些过程。在空间记忆任务中，Syt3 敲除的小鼠正常学习，但表现出缺乏遗忘。在野生型背景下破坏 Syt3:GluA2 结合可模拟缺乏 LTP 衰减和缺乏遗忘，而这些效应在 Syt3 敲除背景下被阻断。我们的研究结果为 Syt3 将 AMPA 受体内化以抑制突触强度和促进遗忘的分子机制提供了证据。
