Laboratoire de Physiologie et Pharmacologie (CP604), Faculté de Médecine, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Bruxelles, Belgium.
Unité de Chronobiologie Théorique (CP231), Faculté des Sciences, Université Libre de Bruxelles, Boulevard du Triomphe, B-1050 Bruxelles, Belgium.
Int J Mol Sci. 2019 Dec 27;21(1):206. doi: 10.3390/ijms21010206.
NMDA receptors (NMDA-R) typically contribute to excitatory synaptic transmission in the central nervous system. While calcium influx through NMDA-R plays a critical role in synaptic plasticity, experimental evidence indicates that NMDAR-mediated calcium influx also modifies neuronal excitability through the activation of calcium-activated potassium channels. This mechanism has not yet been studied theoretically. Our theoretical model provides a simple description of neuronal electrical activity that takes into account the tonic activity of extrasynaptic NMDA receptors and a cytosolic calcium compartment. We show that calcium influx mediated by the tonic activity of NMDA-R can be coupled directly to the activation of calcium-activated potassium channels, resulting in an overall inhibitory effect on neuronal excitability. Furthermore, the presence of tonic NMDA-R activity promotes bistability in electrical activity by dramatically increasing the stimulus interval where both a stable steady state and repetitive firing can coexist. These results could provide an intrinsic mechanism for the constitution of memory traces in neuronal circuits. They also shed light on the way by which β -amyloids can alter neuronal activity when interfering with NMDA-R in Alzheimer's disease and cerebral ischemia.
N-甲基-D-天冬氨酸受体（NMDA-R）通常有助于中枢神经系统中的兴奋性突触传递。虽然 NMDA-R 介导的钙内流在突触可塑性中起着关键作用，但实验证据表明，NMDAR 介导的钙内流也通过激活钙激活钾通道来调节神经元兴奋性。这一机制尚未在理论上进行研究。我们的理论模型提供了一种简单的神经元电活动描述，考虑了突触外 NMDA 受体的紧张活动和细胞质钙池。我们表明，由 NMDA-R 的紧张活动介导的钙内流可以直接与钙激活钾通道的激活偶联，导致神经元兴奋性的总体抑制作用。此外，紧张 NMDA-R 活性的存在通过极大地增加同时存在稳定的稳态和重复放电的刺激间隔，促进电活动的双稳定性。这些结果可以为神经元回路中记忆痕迹的构成提供内在机制。它们还阐明了 β-淀粉样蛋白在阿尔茨海默病和脑缺血中干扰 NMDA-R 时如何改变神经元活性的方式。
