Fedchyshyn Michael J, Wang Lu-Yang
Division of Neurology, The Hospital for Sick Children, Department of Physiology, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada.
J Physiol. 2007 Jun 1;581(Pt 2):581-602. doi: 10.1113/jphysiol.2007.129833. Epub 2007 Mar 8.
The temporal fidelity of synaptic transmission is constrained by the reproducibility of time delays such as axonal conduction delay and synaptic delay, but very little is known about the modulation of these distinct components. In particular, synaptic delay is not generally considered to be modifiable under physiological conditions. Using simultaneous paired patch-clamp recordings from pre- and postsynaptic elements of the calyx of Held synapse, in juvenile mouse auditory brainstem slices, we show here that synaptic activity (20-200 Hz) leads to activity-dependent increases in synaptic delay and its variance as well as desynchronization of evoked responses. Such changes were most robust at 200 Hz in 2 mM extracellular Ca(2+) (Ca(2+)), and could be attenuated by lowering Ca(2+) to 1 mM, increasing temperature to 35 degrees C, or application of the GABA(B)R agonist baclofen, which inhibits presynaptic Ca(2+) currents (I(Ca)). Conduction delay also exhibited slight activity-dependent prolongation, but this prolongation was only sensitive to temperature, and not to Ca(2+) or baclofen. Direct voltage-clamp recordings of I(Ca) evoked by repeated action potential train template (200 Hz) revealed little jitter in the timing and kinetics of I(Ca) under various conditions, suggesting that increases in synaptic delay and its variance occur downstream of Ca(2+) entry. Loading the Ca(2+) chelator EGTA-AM into terminals reduced the progression rate, the extent of activity-dependent increases in various delay components, and their variance, implying that residual Ca(2+) accumulation in the presynaptic nerve terminal induces these changes. Finally, by applying a test pulse at different intervals following a 200 Hz train (150 ms), we demonstrated that prolongation in the various delay components reverses in parallel with recovery in synaptic strength. These observations suggest that a depletion of the readily releasable pool of SVs during high-frequency activity may downregulate not only synaptic strength but also decrease the temporal fidelity of neurotransmission at this and other central synapses.
突触传递的时间保真度受轴突传导延迟和突触延迟等时间延迟可重复性的限制，但对于这些不同组分的调节知之甚少。特别是，突触延迟在生理条件下通常不被认为是可调节的。在幼年小鼠听觉脑干切片中，利用对Held突触花萼的突触前和突触后元件进行同步配对膜片钳记录，我们在此表明，突触活动（20 - 200 Hz）导致突触延迟及其方差的活动依赖性增加以及诱发反应的去同步化。在2 mM细胞外Ca²⁺（[Ca²⁺]ₒ）中，此类变化在200 Hz时最为显著，并且可通过将[Ca²⁺]ₒ降至1 mM、将温度升至35℃或应用GABA(B)R激动剂巴氯芬（其抑制突触前Ca²⁺电流（I(Ca)））来减弱。传导延迟也表现出轻微的活动依赖性延长，但这种延长仅对温度敏感，而对[Ca²⁺]ₒ或巴氯芬不敏感。由重复动作电位序列模板（200 Hz）诱发的I(Ca)的直接电压钳记录显示，在各种条件下I(Ca)的时间和动力学几乎没有抖动，这表明突触延迟及其方差的增加发生在Ca²⁺内流的下游。将Ca²⁺螯合剂EGTA - AM加载到终末会降低进展速率、各种延迟组分的活动依赖性增加程度及其方差，这意味着突触前神经终末中残留的Ca²⁺积累会诱发这些变化。最后，通过在200 Hz序列（150 ms）之后以不同间隔施加测试脉冲，我们证明了各种延迟组分的延长与突触强度的恢复平行逆转。这些观察结果表明，在高频活动期间，突触小泡的易释放池的耗竭可能不仅下调突触强度，还会降低此突触及其他中枢突触处神经传递的时间保真度。
