CNMPB (Centre for Nanoscale Microscopy and Molecular Physiology of the Brain, DFG Research Center 103), Institute of Neuro and Sensory Physiology, Georg-August-University, Göttingen, Germany.
PLoS One. 2018 Sep 26;13(9):e0202802. doi: 10.1371/journal.pone.0202802. eCollection 2018.
Excess glutamate during intense neuronal activity is not instantly cleared and may accumulate in the extracellular space. This has various long-term consequences such as ectopic signaling, modulation of synaptic efficacy and excitotoxicity; the latter implicated in various neurodevelopmental and neurodegenerative diseases. In this study, the quantitative imaging of glutamate homeostasis of hippocampal slices from methyl-CpG binding protein 2 knock-out (Mecp2-/y) mice, a model of Rett syndrome (RTT), revealed unusual repetitive glutamate transients. They appeared in phase with bursts of action potentials in the CA1 neurons. Both glutamate transients and bursting activity were suppressed by the blockade of sodium, AMPA and voltage-gated calcium channels (T- and R-type), and enhanced after the inhibition of HCN channels. HCN and calcium channels in RTT and wild-type (WT) CA1 neurons displayed different voltage-dependencies and kinetics. Both channels modulated postsynaptic integration and modified the pattern of glutamate spikes in the RTT hippocampus. Spontaneous glutamate transients were much less abundant in the WT preparations, and, when observed, had smaller amplitude and frequency. The basal ambient glutamate levels in RTT were higher and transient glutamate increases (spontaneous and evoked by stimulation of Schaffer collaterals) decayed slower. Both features indicate less efficient glutamate uptake in RTT. To explain the generation of repetitive glutamate spikes, we designed a novel model of glutamate-induced glutamate release. The simulations correctly predicted the patterns of spontaneous glutamate spikes observed under different experimental conditions. We propose that pervasive spontaneous glutamate release is a hallmark of Mecp2-/y hippocampus, stemming from and modulating the hyperexcitability of neurons.
在强烈的神经元活动期间，过量的谷氨酸不会立即被清除，可能会在细胞外间隙中积累。这会产生各种长期后果，如异位信号、突触效能的调制和兴奋性毒性；后者与各种神经发育和神经退行性疾病有关。在这项研究中，对 Mecp2 敲除（Mecp2-/y）小鼠（雷特综合征的模型）海马切片的谷氨酸稳态进行定量成像，揭示了异常的重复谷氨酸瞬变。它们出现在 CA1 神经元动作电位爆发的相位中。谷氨酸瞬变和爆发活动都被钠离子、AMPA 和电压门控钙通道（T 型和 R 型）的阻断所抑制，并在 HCN 通道的抑制后增强。RTT 和野生型（WT）CA1 神经元中的 HCN 和钙通道表现出不同的电压依赖性和动力学特性。这两种通道都调节突触后整合，并改变 RTT 海马中的谷氨酸尖峰模式。WT 制剂中自发谷氨酸瞬变的丰度要低得多，而且当观察到自发谷氨酸瞬变时，其幅度和频率都较小。RTT 中的基础环境谷氨酸水平较高，并且瞬态谷氨酸增加（由 Schaffer 侧支刺激引起的自发和诱发）衰减较慢。这两个特征都表明 RTT 中的谷氨酸摄取效率较低。为了解释重复谷氨酸尖峰的产生，我们设计了一种新的谷氨酸诱导谷氨酸释放模型。该模拟正确预测了在不同实验条件下观察到的自发谷氨酸尖峰的模式。我们提出，普遍存在的自发谷氨酸释放是 Mecp2-/y 海马的一个标志，源于并调节神经元的过度兴奋。
