Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus
Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus
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DOI：
10.1016/j.neuroscience.2003.10.033
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Suzuki, E
中科院分区：
文献类型：
--
作者：
Arai, AC;Xia, YF;Suzuki, E
先前的研究表明，正α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体调节剂促进长时程增强（LTP），并改善动物和人类几种类型记忆的形成。然而，这些调节剂在它们对受体动力学和突触传递的作用方面是高度不同的，因此在它们促进突触强度变化的功效方面也可能不同。本研究探讨了三个这些调制器的影响，他们对突触可塑性的领域CA 1海马切片，其中两个苯甲酰胺药物1-（喹喔啉-6-基羰基）哌啶（CX 516）和1-（1，4-苯并二氧杂环己烷-6-基羰基）哌啶（CX 546），显着增强突触传递，但不同的幅度与持续时间的突触反应的相对影响。第三种药物是环噻嗪，它有效地阻断AMPA受体脱敏。通过测量（i）当使用θ-脉冲串刺激时获得稳定增强的可能性（每个脉冲串有三个而不是四个脉冲），（ii）最佳刺激条件下的最大增强量，以及（iii）对长期抑郁（LTD）的影响，评估对可塑性的影响。这两种苯甲酰胺促进形成稳定的增强诱导的三脉冲突发刺激，这通常是无效的。此外，CX 546还将四脉冲突发刺激后的最大诱导增强作用从约50%增加到100%。爆发反应分析表明，CX 546大大延长了去极化的持续时间，通过减缓衰减的反应，从而推测导致更连续的N-甲基-D-天冬氨酸（NMDA）受体激活。环噻嗪是无效的，在增加最大增强无论是外地或全细胞记录。CX 546，而不是CX 516，也增强了近两倍的NMDA受体依赖性的长期抑制引起的异突触2 Hz刺激。用重组NMDA受体（NR 1/NR 2A）进行的试验表明，CX 516和CX 546对这些受体介导的电流没有直接影响。这些结果表明，（1）AMPA受体的调节增加反应幅度或持续时间可以促进LTP的形成，（2）有效减缓反应失活的调节剂增加LTP和LTD的最大幅度，（3）受体脱敏可能对海马中的突触可塑性有轻微影响。我们的数据表明AMPA受体调节剂在增强突触增强或抑制的能力上有很大的不同，这取决于它们对受体动力学的特定影响，并且因此它们在影响诸如存储器编码的高阶过程中也可以是不同有效的。(C)2004年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus.Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.