Department of Physiology and Pharmacology, Robarts Research Institute, University of Western Ontario, London, Ontario.
Hippocampus. 2011 Oct;21(10):1053-61. doi: 10.1002/hipo.20818. Epub 2010 Jun 2.
The induction of long-term potentiation (LTP) of CA3-CA1 synapses requires activation of postsynaptic N-methyl-D-aspartate receptors (GluNRs). At resting potential, the contribution of GluNRs is limited by their voltage-dependent block by extracellular Mg(2+). High-frequency afferent stimulation is required to cause sufficient summation of excitatory synaptic potentials (EPSPs) to relieve this block and to permit an influx of Ca(2+). It has been assumed that this relief of Mg(2+) block is sufficient for induction. We postulated that the induction of LTP also requires a Src-dependent plasticity of GluNRs. Using whole-cell recordings, LTP (GluARs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors-EPSCS was induced by pairing postsynaptic depolarization with presynaptic stimulation. This LTP was both GluNR and Src-dependent, being sensitive to AP-5, a GluNR selective antagonist, or to SU6656, a Src-selective inhibitor. When CNQX was used to block all GluARs, we observed a long-lasting potentiation of GluNR-mediated EPSCs. This plasticity was prevented by transiently blocking GluNRs during the induction protocol or by chelating intracellular Ca(2+). GluNRs plasticity was also prevented by bath applications of SU6656 or intracellular applications of the Src-selective inhibitory peptide, Src(40-58). It was also blocked by preventing activation of protein kinase C, a kinase that is upstream of Src-kinase-dependent regulation of GluNRs. Both GluN2A and GluN2B receptors were found to contribute to the plasticity of GluNRs. The contribution of GluNRs and, in particular, their plasticity to the maintenance of LTP was explored using AP5 and SU6656, respectively. When applied >20 min after induction neither drug influenced the magnitude of LTP. However, when applied immediately after induction, treatment with either drug caused the initial magnitude of LTP to progressively decrease to a sustained phase of reduced amplitude. Collectively, our findings suggest that GluNR plasticity, although not strictly required for induction, is necessary for the maintenance of a nondecrementing component of LTP.
长时程增强（LTP）的诱导需要激活突触后 N-甲基-D-天冬氨酸受体（GluNRs）。在静息电位下，GluNRs 的贡献受到细胞外镁（Mg(2+)）的电压依赖性阻断的限制。需要高频传入刺激来引起足够的兴奋性突触后电位（EPSPs）的总和，以解除这种阻断并允许 Ca(2+)内流。人们一直认为，这种 Mg(2+)阻断的解除足以诱导 LTP。我们假设，LTP 的诱导还需要 GluNRs 的Src 依赖性可塑性。使用全细胞记录，通过突触后去极化与突触前刺激配对诱导 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体-EPSCS 的 LTP（GluARs）。这种 LTP 既依赖于 GluNR，也依赖于 Src，对 AP-5（一种 GluNR 选择性拮抗剂）或 SU6656（一种 Src 选择性抑制剂）敏感。当使用 CNQX 阻断所有 GluAR 时，我们观察到 GluNR 介导的 EPSCs 的持久增强。这种可塑性在诱导方案期间短暂阻断 GluNR 或螯合细胞内 Ca(2+)时被阻止。SU6656 或细胞内应用 Src 选择性抑制肽 Src(40-58)也阻止了 GluNR 可塑性。通过防止蛋白激酶 C 的激活也阻止了 GluNR 的可塑性，蛋白激酶 C 是 Src 激酶依赖性调节 GluNR 的上游激酶。发现 GluN2A 和 GluN2B 受体都有助于 GluNR 的可塑性。使用 AP5 和 SU6656 分别探索了 GluNRs 的贡献，特别是它们的可塑性，对 LTP 的维持的贡献。在诱导后 >20 分钟应用时，两种药物均不影响 LTP 的幅度。然而，在诱导后立即应用时，两种药物的处理均导致 LTP 的初始幅度逐渐降低至幅度降低的持续阶段。总的来说，我们的发现表明，尽管 GluNR 可塑性不是诱导所必需的，但对于维持非递减的 LTP 成分是必要的。
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