Computational Neuroscience Unit, Okinawa Institute of Science and Technology, 1919-1 Tancha, Onna-Son, Okinawa 904-0495, Japan.
Neural Netw. 2013 Nov;47:3-10. doi: 10.1016/j.neunet.2012.11.015. Epub 2012 Dec 7.
A stochastic model of the signaling network responsible for the induction of long-term depression (LTD) at the parallel fiber to Purkinje cell synapse is described. The model includes a PKC-ERK-cPLA2 positive feedback loop and mechanisms of AMPA receptor trafficking. It was tuned to replicate calcium uncaging experiments that cause LTD. The ultrasensitive activation of ERK makes the signaling network activity bistable, causing either LTD or not. Therefore, in single synapses only two discrete stable states (LTD and non-LTD) can be expressed. The stochastic properties of the signaling network causes threshold dithering and probabilistic expression of LTD, which allows at the macroscopic level for many different and stable mean magnitudes of depression. When the volume of a single spine is simulated no thresholds for the calcium input signal are present. Such thresholds appear only when the volume of simulation is increased by a factor 100 or more and the model output is then bistable. Similarly, deterministic solutions of the same model show only bistable behavior. LTD induction requires activation of the PKC-ERK-cPLA2 positive feedback loop but this activity is not constant: the activities of ERK and of cPLA2 fluctuate strongly. This is much less the case for PKC which is more constantly activated and thereby promotes a stable output of the pathway.
描述了一个负责诱导浦肯野细胞平行纤维突触长时程抑制（LTD）的信号转导网络的随机模型。该模型包括一个 PKC-ERK-cPLA2 正反馈回路和 AMPA 受体运输的机制。它被调整为复制导致 LTD 的钙光解实验。ERK 的超敏激活使信号转导网络的活动呈双稳态，导致 LTD 或不发生。因此，在单个突触中只能表达两种离散的稳定状态（LTD 和非 LTD）。信号转导网络的随机特性导致阈值抖动和 LTD 的概率表达，这使得在宏观水平上可以表达许多不同的稳定的抑制程度。当模拟单个棘突的体积时，钙输入信号不存在阈值。只有当模拟体积增加 100 倍或更多，并且模型输出呈双稳态时，才会出现这种阈值。同样，相同模型的确定性解也只表现出双稳态行为。LTD 的诱导需要激活 PKC-ERK-cPLA2 正反馈回路，但这种活性不是恒定的：ERK 和 cPLA2 的活性波动很大。PKC 的情况要少得多，它更持续地被激活，从而促进了通路的稳定输出。
