Castellani G C, Quinlan E M, Cooper L N, Shouval H Z
Physics Department, CIG and Dimorfipa Bologna University, Bologna 40121, Italy.
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12772-7. doi: 10.1073/pnas.201404598.
In many regions of the brain, including the mammalian cortex, the magnitude and direction of activity-dependent changes in synaptic strength depend on the frequency of presynaptic stimulation (synaptic plasticity), as well as the history of activity at those synapses (metaplasticity). We present a model of a molecular mechanism of bidirectional synaptic plasticity based on the observation that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD) correlate with the phosphorylation/dephosphorylation of sites on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit protein GluR1. The primary assumption of the model, for which there is wide experimental support, is that postsynaptic calcium concentration and consequent activation of calcium-dependent protein kinases and phosphatases are the triggers for the induction of LTP/LTD. As calcium influx through the n-methyl-d-aspartate (NMDA) receptor plays a fundamental role in the induction of LTP/LTD, changes in the properties of NMDA receptor-mediated calcium influx will dramatically affect activity-dependent synaptic plasticity (metaplasticity). We demonstrate that experimentally observed metaplasticity can be accounted for by activity-dependent regulation of NMDA receptor subunit composition and function. Our model produces a frequency-dependent LTP/LTD curve with a sliding synaptic modification threshold similar to what has been proposed theoretically by Bienenstock, Cooper, and Munro and observed experimentally.
在大脑的许多区域，包括哺乳动物的皮层，突触强度依赖于活动的变化幅度和方向取决于突触前刺激的频率（突触可塑性），以及这些突触处的活动历史（元可塑性）。基于长期突触增强（LTP）和长期突触抑制（LTD）与α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体亚基蛋白GluR1上位点的磷酸化/去磷酸化相关这一观察结果，我们提出了一种双向突触可塑性分子机制的模型。该模型的主要假设得到了广泛的实验支持，即突触后钙浓度以及随之而来的钙依赖性蛋白激酶和磷酸酶的激活是诱导LTP/LTD的触发因素。由于通过N-甲基-D-天冬氨酸（NMDA）受体的钙内流在LTP/LTD的诱导中起基本作用，NMDA受体介导的钙内流特性的变化将极大地影响依赖于活动的突触可塑性（元可塑性）。我们证明，实验观察到的元可塑性可以通过NMDA受体亚基组成和功能的活动依赖性调节来解释。我们的模型产生了一条频率依赖性的LTP/LTD曲线，其突触修饰阈值类似于Bienenstock、Cooper和Munro从理论上提出并通过实验观察到的曲线。
