Distinguishing between Presynaptic and Postsynaptic Mechanisms of Short-Term Depression during Action Potential Trains
Distinguishing between Presynaptic and Postsynaptic Mechanisms of Short-Term Depression during Action Potential Trains
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DOI：
10.1523/jneurosci.23-12-04868.2003
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发表时间：
2003-06
期刊：
影响因子：
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通讯作者：
Adrian Y. C. Wong;B. Graham;B. Billups;I. Forsythe
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文献类型：
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作者：
Adrian Y. C. Wong;B. Graham;B. Billups;I. Forsythe
短期易化和抑郁对许多谷氨酸能突触的传递有深远的影响，特别是在一连串刺激过程中。这些过程的一个主要组成部分是突触后受体脱敏。突触前和突触后的机制都可以促进突触的疗效，但通常很难定义它们各自的贡献。可以使用脱敏阻滞剂，如环噻嗪(CTZ)，但这些药物中的许多对递质释放具有非特异性影响，使在生理条件下定义突触有效性的尝试复杂化。我们描述并验证了一种新的方法，以低亲和力竞争性谷氨酸受体拮抗剂γ-d-谷氨酰甘氨酸或犬尿酸为基础，最大限度地减少突触刺激过程中的脱敏。AMPA受体动力学的计算模型表明，这一机制可以通过AMPA受体的简单竞争性拮抗来解释，其中拮抗剂的快速关闭速度允许在刺激间隔期间阻断和未阻断的池之间重新平衡。我们在Hold的花萼上的结果表明，在10 Hz以下的频率下，脱敏对突触抑制的贡献很小，但在更高的频率下，脱敏对突触抑制有重要的贡献，累积的脱敏掩盖了短期的促进作用，并导致对量子含量的低估。这种保护脱敏的新方法与生理学研究相一致，但不能与CTZ联合使用。虽然突触前小泡耗竭是导致短期抑郁的主要因素，但我们的结果表明，AMPA受体失敏在听觉突触起病后以一种频率依赖的方式对抑郁起作用。
Short-term facilitation and depression have a profound influence on transmission at many glutamatergic synapses, particularly during trains of stimuli. A major component of these processes is postsynaptic receptor desensitization. Both presynaptic and postsynaptic mechanisms can contribute to synaptic efficacy, but it is often difficult to define their respective contributions. Blockers of desensitization such as cyclothiazide (CTZ) can be used, but many of these drugs have nonspecific effects on transmitter release, complicating attempts to define synaptic effectiveness under physiological conditions. We describe and validate a new method to minimize desensitization during trains of synaptic stimuli that is based on the low-affinity competitive glutamate receptor antagonists γ-d-glutamylglycine or kynurenic acid. A computational model of AMPA receptor kinetics shows that the mechanism can be accounted for by simple competitive antagonism of AMPA receptors, where the rapid off-rate of the antagonist permits re-equilibration between blocked and unblocked pools during the interstimulus interval. Our results at the calyx of Held show that desensitization makes little contribution to synaptic depression at frequencies below 10 Hz, but at higher frequencies it makes an important contribution, with accumulating desensitization masking short-term facilitation and causing an underestimation of quantal content. This novel method of protection from desensitization is compatible with physiological studies but cannot be used in conjunction with CTZ. Although presynaptic vesicle depletion makes the dominant contribution to short-term depression, our results show that AMPA receptor desensitization contributes to the depression at auditory synapses after hearing onset and in a frequency-dependent manner.