NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity.
NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity.
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突触输入的 NMDAR 依赖性体细胞增强与 β 淀粉样蛋白介导的神经元过度活跃相关
DOI：
10.1186/s40035-021-00260-3
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发表时间：
2021-09-08
影响因子：
12.6
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Bao Y;Yang X;Fu Y;Li Z;Gong R;Lu W
β淀粉样蛋白（β Amyloid，Aβ）介导的神经元过度活动是阿尔茨海默病（Alzheimer's disease，AD）早期的一个重要特征，近年来研究发现A β介导的神经元过度活动是由谷氨酸再摄取抑制引起的。然而，受损的谷氨酸再摄取导致神经元过度活跃的潜在机制仍不清楚。谷氨酸再摄取的慢性抑制导致周围谷氨酸的积累，其可以从树突处的突触位点扩散到索马，以提高体细胞N-甲基-D-天冬氨酸受体（NMDAR）的紧张性激活。然而，很少有人关注位于神经元索马的突触外谷氨酸受体（GluRs）的紧张性活动变化在神经元过度活动产生中的潜在作用。采用全细胞膜片钳技术，观察了TFB-苏型-β-苄氧基天冬氨酸（TBOA）和人Aβ1-42肽寡聚体对海马CA 1区锥体神经元的影响。在离索马不同距离处进行一系列树突膜片钳记录，以确定突触输入变化的位置。此外，在细胞贴附模式下进行单通道记录，以研究索马的单个NMDAR的活性变化。用TBOA或人Aβ1-42肽寡聚体阻断谷氨酸摄取引起CA 1海马神经元突触输入增强。引人注目的是，这种增强作用特别发生在索马，这取决于体细胞含GluN 2B的NMDARs（GluN 2B-NMDARs）的激活，并伴随着体细胞NMDARs开放概率的实质性和持续性增加。阻断索马的GluN 2B-NMDAR活性可完全逆转TBOA或Aβ1-42诱导的躯体增强和神经元活动过度。突触输入的体细胞增强可能代表了一种新的放大机制，该机制提高了细胞的兴奋性，从而导致AD中谷氨酸再摄取受损引起的神经元活动过度。在线版本包含补充材料，可通过10.1186/s40035-021-00260-3获得。
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 Aβ1–42 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 Aβ1–42 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 Aβ1–42-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. The online version contains supplementary material available at 10.1186/s40035-021-00260-3.
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影响因子：
82.9
作者：
Citron, M;Westaway, D;Selkoe, DJ
通讯作者：
Selkoe, DJ
DOI：
10.1126/science.1169096
发表时间：
2009-02-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kuchibhotla KV;Lattarulo CR;Hyman BT;Bacskai BJ
通讯作者：
Bacskai BJ
DOI：
10.1523/jneurosci.0203-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
64.5
作者：
Papouin, Thomas;Ladepeche, Laurent;Oliet, Stephane H. R.
通讯作者：
Oliet, Stephane H. R.
影响因子：
3.4
作者：
Nahum-Levy, R;Lipinski, D;Benveniste, M
通讯作者：
Benveniste, M