It is well--established that Rab11-dependent recycling endosomes drive the activity-dependent delivery of AMPA receptors (AMPARs) into synapses during long-term potentiation (LTP). Nevertheless, the molecular basis for this specialized function of recycling endosomes is still unknown. Here, we have investigated RAB11FIP2 (FIP2 hereafter) as a potential effector of Rab11-dependent trafficking during LTP in rat hippocampal slices. Surprisingly, we found that FIP2 operates independently from Rab11 proteins, and acts as a negative regulator of AMPAR synaptic trafficking. Under basal conditions, FIP2 associates with AMPARs at immobile compartments, separately from recycling endosomes. Using shRNA-mediated knockdown, we found that FIP2 prevents GluA1 (encoded by the Gria1 gene) AMPARs from reaching the surface of dendritic spines in the absence of neuronal stimulation. Upon induction of LTP, FIP2 is rapidly mobilized, dissociates from AMPARs and undergoes dephosphorylation. Interestingly, this dissociation of the FIP2-AMPAR complex, together with FIP2 dephosphorylation, is required for LTP, but the interaction between FIP2 and Rab11 proteins is not. Based on these results, we propose a retention-release mechanism, where FIP2 acts as a gate that restricts the trafficking of AMPARs, until LTP induction triggers their release and allows synaptic delivery.

中文翻译：

---

基于RAB11FIP2的保持释放机制可在长期增强过程中实现AMPA受体突触传递。

公认的是Rab11依赖的循环内体在长期增强（LTP）期间驱动AMPA受体（AMPAR）的活性依赖传递到突触中。然而，回收内体这种特殊功能的分子基础仍然是未知的。在这里，我们已经调查了RAB11FIP2（以下称FIP2）作为大鼠海马切片LTP期间Rab11依赖性转运的潜在效应物。出人意料的是，我们发现FIP2独立于Rab11蛋白运行，并充当AMPAR突触运输的负调节剂。在基础条件下，FIP2与固定隔室的AMPAR结合，与回收内体分开。使用shRNA介导的敲低，我们发现，在没有神经元刺激的情况下，FIP2可以阻止GluA1（由Gria1基因编码）AMPAR到达树突棘的表面。诱导LTP后，FIP2迅速动员，从AMPAR分离并进行去磷酸化。有趣的是，LTP需要FIP2-AMPAR复合物的这种解离以及FIP2的去磷酸化，但是FIP2和Rab11蛋白之间的相互作用不是必需的。基于这些结果，我们提出了一种保留释放机制，其中FIP2充当限制AMPAR转运的门，直到LTP诱导触发其释放并允许突触传递。LTP需要与FIP2脱磷酸一起使用，但是FIP2和Rab11蛋白之间的相互作用不是必需的。根据这些结果，我们提出了一种保留释放机制，其中FIP2充当限制AMPAR转运的门，直到LTP诱导触发其释放并允许突触传递。LTP需要与FIP2脱磷酸一起使用，但是FIP2和Rab11蛋白之间的相互作用不是必需的。基于这些结果，我们提出了一种保留释放机制，其中FIP2充当限制AMPAR转运的门，直到LTP诱导触发其释放并允许突触传递。