Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein–protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

中文翻译：

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海马 LTP 和情境学习需要 AMPA 受体的表面扩散

长期以来，兴奋性突触传递的长时程增强 (LTP) 一直被认为是学习和记忆的细胞相关因素。早期的 LTP（不到 1 小时）最初被解释为突触前谷氨酸释放增加或突触后 AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体功能的直接修饰。令人信服的模型最近提出，突触增强可以通过招募额外的突触后 AMPA 受体 (AMPARs) 发生，AMPARs 来自细胞内储备库，或者来自神经元表面预先存在的附近突触外受体。然而，在早期 LTP 期间突触可以快速招募新 AMPAR 的确切机制仍然未知。特别是，仍然缺乏关于 AMPAR 表面扩散作为突触可塑性中的运输机制的关键作用的直接证据。在这里，我们使用 AMPAR 固定方法表明，在培养切片、急性切片和体内，干扰 AMPAR 表面扩散会显着损害 Schaffer 侧支的突触增强和对小鼠海马 CA1 区域的连合输入。我们的数据还确定了各种 AMPAR 贩运路线对突触增强的时间分布的不同贡献。此外，背侧海马体内的 AMPAR 固定抑制了恐惧条件反射，表明 AMPAR 扩散对于情境学习的早期阶段很重要。所以，我们的结果直接证明了通过表面扩散向突触募集新受体是 LTP 和海马学习表达的关键机制。由于 AMPAR 表面扩散受弱布朗力控制，而这些力很容易受到蛋白质-蛋白质相互作用的干扰，我们预计这种基本的运输机制将成为调节突触增强和学习的关键目标。