Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I.
Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I.
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DOI：
10.1523/jneurosci.1746-10.2010
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发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Soderling TR
中科院分区：
文献类型：
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作者：
Fortin DA;Davare MA;Srivastava T;Brady JD;Nygaard S;Derkach VA;Soderling TR
它是公认的，LTP，学习和记忆的范例，结果在一个稳定的扩大与招聘额外的GluA 1-含有AMPAR增强棘。虽然涉及肌动蛋白细胞骨架的调节，但负责这种棘扩张的详细信号传导机制尚不清楚。在这里，我们使用培养的成熟海马神经元刺激甘氨酸诱导的，突触特异性形式的化学LTP（GI-LTP）。我们报告说，稳定的结构塑性（即，伴随GI-LTP的脊髓头部增大和脊髓长度缩短）被NMDAR（APV）或CaM-激酶激酶（STO-609）（CaM-激酶I（CaMKI）的上游激活剂）的抑制剂阻断，以及被显性阴性（dn）CaMKI而不是dnCaMKIV转染阻断。招募GluA 1的脊柱表面发生后GI-LTP和模仿转染组成型活性CaMKI。转染GluA 1诱导的脊柱扩大与Ca 2+渗透性AMPAR（CP-AMPAR）的突触募集相关，通过增加mEPSC的整流指数及其对IEM-1460（CP-AMPAR的选择性拮抗剂）的敏感性进行评估。此外，由GI-LTP本身引起的脊柱尺寸和mEPSC振幅的增加被IEM-1460阻断，表明CP-AMPAR的参与。通过IEM-1460对其激活的抑制鉴定的CP-AMPAR的下游信号传导效应物包括调节棘肌动蛋白动力学的Rac/PAK/LIM-激酶途径。总之，我们的研究结果表明，通过CaMKI的CP-AMPAR的突触募集可能提供了NMDAR激活LTP和调节的信号通路，通过肌动蛋白聚合驱动脊柱扩大之间的机制联系。
It is well-established that LTP, a paradigm for learning and memory, results in a stable enlargement of potentiated spines associated with recruitment of additional GluA1-containing AMPARs. Although regulation of the actin cytoskeleton is involved, the detailed signaling mechanisms responsible for this spine expansion are unclear. Here we used cultured mature hippocampal neurons stimulated with a Glycine-Induced, synapse-specific form of chemical LTP (GI-LTP). We report that the stable structural plasticity (i.e., spine head enlargement and spine length shortening) that accompanies GI-LTP was blocked by inhibitors of NMDARs (APV) or CaM-kinase kinase (STO-609), the upstream activator of CaM-kinase I (CaMKI), as well as by transfection with dominant-negative (dn) CaMKI but not dnCaMKIV. Recruitment of GluA1 to the spine surface occurred following GI-LTP and was mimicked by transfection with constitutively-active CaMKI. Spine enlargement induced by transfection of GluA1 was associated with synaptic recruitment of Ca2+-permeable AMPARs (CP-AMPARs) as assessed by an increase in the rectification index of mEPSCs and their sensitivity to IEM-1460, a selective antagonist of CP-AMPARs. Furthermore, the increase in spine size and mEPSC amplitude resulting from GI-LTP itself was blocked by IEM-1460, demonstrating involvement of CP-AMPARs. Downstream signaling effectors of CP-AMPARs, identified by suppression of their activation by IEM-1460, included the Rac/PAK/LIM-kinase pathway that regulates spine actin dynamics. Taken together, our results suggest that synaptic recruitment of CP-AMPARs via CaMKI may provide a mechanistic link between NMDAR activation in LTP and regulation of a signaling pathway that drives spine enlargement via actin polymerization.