Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors.
Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors.
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DOI：
10.1038/nature23658
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发表时间：
2017-09-21
期刊：
影响因子：
64.8
通讯作者：
Choquet D
中科院分区：
文献类型：
--
作者：
Penn AC;Zhang CL;Georges F;Royer L;Breillat C;Hosy E;Petersen JD;Humeau Y;Choquet D
长期以来，兴奋性突触传递的长时程增强（LTP）一直被认为与学习和记忆有关。早期LTP（eLTP，<1小时）最初被解释为突触前谷氨酸释放的增加或突触后α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）功能的直接修饰。令人信服的模型最近提出，突触增强可以通过额外的突触后AMPAR的募集而发生，这些AMPAR来源于通过胞吐作用的细胞内储备池或来源于预先存在于神经元表面上的附近的突触外受体。然而，突触在eLTP期间可以快速招募新AMPAR的确切机制仍然未知。特别是，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仍然缺乏。使用AMPAR固定的方法，我们表明，干扰AMPAR表面扩散显着受损的突触增强Schaffer侧支/连合输入角氨区1（CA 1）在培养的切片，急性切片和在体内。我们的数据还确定了不同的AMPAR贩运路线的突触增强的时间分布的不同贡献。此外，AMPAR固定在体内背海马（DH）恐惧条件反射前，表明AMPAR扩散的早期阶段的背景学习是重要的。因此，我们的研究结果提供了一个直接的证据，即通过表面扩散的新受体的突触的招聘是一个关键的机制表达的LTP和海马学习。由于AMPAR表面扩散是由弱布朗力，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是一个关键的目标，用于调节突触增强和学习。
Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (eLTP, <1 hour) had initially been explained either by presynaptic increases in glutamate release or by direct modification of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional post-synaptic 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 eLTP is still unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion dramatically impaired synaptic potentiation of Schaffer collateral/commissural inputs to cornu ammonis area 1 (CA1) in cultured slices, acute slices and in vivo. Our data also identifies distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus (DH) before fear conditioning, indicated 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.
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