Desensitization properties of AMPA receptors at the cerebellar mossy fiber granule cell synapse.
Desensitization properties of AMPA receptors at the cerebellar mossy fiber granule cell synapse.
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DOI：
10.1523/jneurosci.2399-07.2007
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发表时间：
2007-08-01
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影响因子：
--
通讯作者：
Silver RA
中科院分区：
文献类型：
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作者：
DiGregorio DA;Rothman JS;Nielsen TA;Silver RA
天然AMPA受体（AMPAR）在谷氨酸的持续存在下表现出快速和深刻的脱敏。因此，脱敏作用导致谷氨酸积累的突触出现短期抑制。在不表现出脱敏依赖性抑制的突触中，AMPAR被认为是受到保护的，免于长期或重复暴露于突触释放的谷氨酸。在小脑苔藓纤维（MF）的颗粒细胞（GC）突触，其中高释放概率和谷氨酸溢出产生大量积累的谷氨酸浓度的间隙（[Glut]间隙）在高频传输过程中，只有中度脱敏的阶段AMPAR EPSC发生。为了研究这种电流是如何产生的，我们使用谷氨酸释放研究了GC中突触AMPAR的动力学特性。光解4-甲氧基-7-硝基吲哚啉-笼L-谷氨酸盐（MNI-谷氨酸盐）与大的照明点产生阶梯状增加[Glut]裂缝，可用于系统地探测AMPAR动力学。在低水平的激活，突触AMPAR表现出很少的脱敏。随着较大的激活，脱敏时间过程变得更快，但脱敏水平仅弱依赖于受体占有率。事实上，大量的抗脱敏电流成分仍然（17%）在饱和谷氨酸。光解与小照明点产生短暂的[谷氨酸]裂缝波形和瞬态AMPAR激活，类似的EPSC电流分量。与这样的斑点配对脉冲uncaging显示溢出样激活后的脱敏和适度的抑郁症后，模仿量子和溢出组件一起激活。我们的研究结果表明，GC AMPAR表现出在低occupancy脱敏的阻力，这一属性是至关重要的维持在谷氨酸积累的突触的高频传输。
Native AMPA receptors (AMPARs) exhibit rapid and profound desensitization in the sustained presence of glutamate. Desensitization therefore contributes to short-term depression at synapses in which glutamate accumulates. At synapses that do not exhibit desensitization-dependent depression, AMPARs are thought to be protected against prolonged or repetitive exposure to synaptically released glutamate. At the cerebellar mossy fiber (MF) to granule cell (GC) synapse, in which high release probability and glutamate spillover produce a substantial buildup of glutamate concentration in the cleft ([Glut]cleft) during high-frequency transmission, only moderate desensitization of the phasic AMPAR EPSC occurs. To investigate how such currents are produced, we examined the kinetic properties of synaptic AMPARs in GCs using glutamate uncaging. Photolysis of 4-methoxy-7-nitroindolinyl-caged L-glutamate (MNI-glutamate) with large illumination spots produced step-like increases in [Glut]cleft that could be used to systematically probe AMPAR kinetics. At low levels of activation, synaptic AMPARs exhibited little desensitization. With larger activations, the desensitization time course became faster, but the level of desensitization was only weakly dependent on receptor occupancy. Indeed, a substantial desensitization-resistant current component remained (17%) in saturating glutamate. Photolysis with small illumination spots produced brief [Glut]cleft waveforms and transient AMPAR activations, similar to the EPSC current components. Paired-pulse uncaging with such spots revealed little desensitization after spillover-like activations and modest depression after activations that mimicked quantal and spillover components together. Our results show that GC AMPARs exhibit a resistance to desensitization at low occupancies and that this property is crucial for sustaining high-frequency transmission at a synapse in which glutamate accumulates.