Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage
Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage
复制标题
DOI：
10.1523/jneurosci.4289-14.2015
复制
发表时间：
2015-09-02
影响因子：
5.3
通讯作者：
Zito, Karen
中科院分区：
文献类型：
--
作者：
Stein, Ivar S.;Gray, John A.;Zito, Karen
树突棘突触的消除是大脑皮层发育过程中神经元回路细化的关键步骤。多项研究表明，活动引起的树突棘收缩和回缩取决于 NMDA 型谷氨酸受体 (NMDAR) 的激活，NMDA 型谷氨酸受体 (NMDAR) 的激活会导致细胞外钙离子的流入和钙依赖性磷酸酶的激活，从而改变树突棘细胞骨架的调节因子，这表明细胞外钙离子的流入会驱动树突棘收缩。有趣的是，最近的一份报告揭示了 NMDAR 在调节突触强度方面的一种新型非离子型功能，该功能依赖于谷氨酸结合，但与通过受体的离子通量无关（Nabavi 等人，2013）。在这里，我们测试了非离子型 NMDAR 信号传导是否也能在驱动树突棘的结构可塑性中发挥作用。利用大鼠海马 CA1 神经元的双光子谷氨酸解笼锁和延时成像，我们发现，即使存在 NMDAR D-丝氨酸/甘氨酸结合位点拮抗剂 7-氯犬尿氨酸 (7CK)，低频谷氨酸刺激也会导致树突棘收缩，从而完全阻断 NMDAR 介导的电流和 Ca2+ 瞬变。值得注意的是，7CK 或 MK-801 的应用还将高频解笼刺激引起的脊柱扩大转化为脊柱收缩，表明通过 NMDAR 的强烈 Ca2+ 流入通常会克服非离子收缩信号以驱动脊柱生长。我们的结果支持一个模型，其中 NMDAR 信号传导独立于离子通量，驱动多刺突触的结构收缩。
The elimination of dendritic spine synapses is a critical step in the refinement of neuronal circuits during development of the cerebral cortex. Several studies have shown that activity-induced shrinkage and retraction of dendritic spines depend on activation of the NMDA-type glutamate receptor (NMDAR), which leads to influx of extracellular calcium ions and activation of calcium-dependent phosphatases that modify regulators of the spine cytoskeleton, suggesting that influx of extracellular calcium ions drives spine shrinkage. Intriguingly, a recent report revealed a novel non-ionotropic function of the NMDAR in the regulation of synaptic strength, which relies on glutamate binding but is independent of ion flux through the receptor (Nabavi et al., 2013). Here, we tested whether non-ionotropic NMDAR signaling could also play a role in driving structural plasticity of dendritic spines. Using two-photon glutamate uncaging and time-lapse imaging of rat hippocampal CA1 neurons, we show that low-frequency glutamatergic stimulation results in shrinkage of dendritic spines even in the presence of the NMDAR D-serine/ glycine binding site antagonist 7-chlorokynurenic acid (7CK), which fully blocks NMDAR-mediated currents and Ca2+ transients. Notably, application of 7CK or MK-801 also converts spine enlargement resulting from a high-frequency uncaging stimulus into spine shrinkage, demonstrating that strong Ca2+ influx through the NMDAR normally overcomes a non-ionotropic shrinkage signal to drive spine growth. Our results support a model in which NMDAR signaling, independent of ion flux, drives structural shrinkage at spiny synapses.