Kinetics of Mg2+ unblock of NMDA receptors:: implications for spike-timing dependent synaptic plasticity
Kinetics of Mg2+ unblock of NMDA receptors:: implications for spike-timing dependent synaptic plasticity
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DOI：
10.1113/jphysiol.2003.058842
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发表时间：
2004-04-15
影响因子：
5.5
通讯作者：
Stuart, GJ
中科院分区：
文献类型：
--
作者：
Kampa, BM;Clements, J;Stuart, GJ
NMDA受体（NMDAR）的Mg 2+阻断和解除阻断的时间过程决定了它们被去极化激活的程度。在这里，我们直接测量NMDAR通道开放的速率响应于去极化后，在不同的时间短暂（1毫秒）和持续（4.6秒）的应用程序谷氨酸从新皮层锥体神经元的有核补丁。Mg ~（2+）的解阻滞动力学是一个非瞬时的复杂过程，由一个显著的快成分（时间常数约为100 μ s）和慢成分（时间常数为4和300 ms）组成，其相对幅度取决于去极化脉冲的时间。拟合动力学模型，这些数据表明，Mg 2+不仅阻断NMDAR通道，但降低开放概率和亲和力谷氨酸，同时增强脱敏。这些效应以时间依赖性方式减缓响应于去极化的NMDAR通道开放的速率，使得在谷氨酸盐应用后的稍后时间的去极化期间，Mg 2+解除阻断的较慢组分增强。这一点的一个生理结果是，在谷氨酸盐应用后较早发生的短暂去极化能够更好地打开NMDAR通道。这一发现对尖峰定时依赖性突触可塑性（STDP）具有重要意义，其中动作电位相对于突触输入的精确（毫秒）定时决定了突触强度变化的幅度和符号。事实上，我们发现，由真实的树突状动作电位波形引起的NMDAR通道激活的STDP定时曲线比假设瞬时Mg 2+解除阻断的预期窄，表明NMDAR通道的缓慢Mg 2+解除阻断使STDP定时窗口更精确。
The time course of Mg2+ block and unblock of NMDA receptors (NMDARs) determines the extent they are activated by depolarization. Here, we directly measure the rate of NMDAR channel opening in response to depolarizations at different times after brief (1 ms) and sustained (4.6 s) applications of glutamate to nucleated patches from neocortical pyramidal neurons. The kinetics of Mg2+ unblock were found to be non-instantaneous and complex, consisting of a prominent fast component (time constant similar to100 mus) and slower components (time constants 4 and 300 ms), the relative amplitudes of which depended on the timing of the depolarizing pulse. Fitting a kinetic model to these data indicated that Mg2+ not only blocks the NMDAR channel, but reduces both the open probability and affinity for glutamate, while enhancing desensitization. These effects slow the rate of NMDAR channel opening in response to depolarization in a time-dependent manner such that the slower components of Mg2+ unblock are enhanced during depolarizations at later times after glutamate application. One physiological consequence of this is that brief depolarizations occurring earlier in time after glutamate application are better able to open NMDAR channels. This finding has important implications for spike-timing-dependent synaptic plasticity (STDP), where the precise (millisecond) timing of action potentials relative to synaptic inputs determines the magnitude and sign of changes in synaptic strength. Indeed, we find that STDP timing curves of NMDAR channel activation elicited by realistic dendritic action potential waveforms are narrower than expected assuming instantaneous Mg2+ unblock, indicating that Slow Mg2+ unblock of NMDAR channels makes the STDP timing window more precise.