MOE Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, 210096, China.
Department of Neurology, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontier Center for Brain Science, Fudan University, Shanghai, 200032, China.
Transl Neurodegener. 2021 Sep 8;10(1):34. doi: 10.1186/s40035-021-00260-3.
β Amyloid (Aβ)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity.
Whole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma.
Blocking glutamate uptake with either TBOA or the human Aβ peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aβ-induced somatic potentiation and neuronal hyperactivity.
The somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.
β淀粉样蛋白（Aβ）介导的神经元过度兴奋是阿尔茨海默病（AD）早期的一个关键特征，最近有研究提出其是由谷氨酸摄取的抑制引发的。然而，导致谷氨酸摄取受损引起神经元过度兴奋的潜在机制仍不清楚。谷氨酸摄取的慢性抑制会导致周围谷氨酸的积累，这些谷氨酸可以从树突上的突触部位扩散到神经元胞体，从而增加体细胞 N-甲基-D-天冬氨酸受体（NMDARs）的紧张激活。然而，对于位于神经元胞体上的突触外谷氨酸受体（GluRs）的紧张活动变化在神经元过度兴奋中的潜在作用，关注较少。
在急性海马脑片上，用 TFB-threo-β-苯甲氧基天冬氨酸（TBOA）或人 Aβ 肽寡聚物处理 CA1 锥体神经元，进行全细胞膜片钳记录。在不同距离从胞体进行一系列树突片钳记录，以确定突触输入变化的位置。此外，采用细胞贴附模式进行单通道记录，以研究胞体上单个 NMDAR 的活性变化。
用 TBOA 或人 Aβ 肽寡聚物阻断谷氨酸摄取会增强 CA1 海马神经元的突触输入。引人注目的是，这种增强作用特异性地发生在胞体上，这取决于含有 GluN2B 的体细胞 NMDARs（GluN2B-NMDARs）的激活，并伴有体细胞 NMDAR 开放概率的实质性和持续增加。阻断胞体上 GluN2B-NMDARs 的活性可完全逆转 TBOA 诱导或 Aβ 诱导的胞体增强作用和神经元过度兴奋。
突触输入的胞体增强可能代表一种新的放大机制，可提高细胞兴奋性，从而有助于 AD 中因谷氨酸摄取受损而引发的神经元过度兴奋。
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