Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors.
Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors.
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DOI：
10.3390/ijms22126298
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发表时间：
2021-06-11
影响因子：
5.6
通讯作者：
von Engelhardt J
中科院分区：
文献类型：
--
作者：
Back MK;Ruggieri S;Jacobi E;von Engelhardt J
阿尔茨海默病（AD）发病和进展的病理生理在脑区域之间是不同的。例如，新皮层是在阿尔茨海默病早期就受到影响的大脑区域。NMDA受体（NMDARs）参与介导β淀粉样蛋白（Aβ）毒性。另一方面，NMDAR的表达可受Aβ的影响。我们测试了新皮质神经元对a β毒性的高度易感性是否可能是由于特定的NMDAR表达谱或a β对NMDAR表达的特定调节所致。电生理分析表明，6月龄野生型小鼠锥体细胞主要表达GluN1/GluN2A NMDARs。虽然5xFAD小鼠突触nmdar介导的电流没有改变，但突触外nmdar似乎含有GluN1/GluN2A和GluN1/GluN2A/GluN2B。我们使用条件GluN1和GluN2B敲除小鼠来研究NMDARs是否与a β毒性有关。病毒介导的a β-过表达3周后，5xFAD小鼠锥体细胞棘数减少，神经元棘数增加。a β介导的脊柱数目和功能性突触的改变都需要NMDARs。因此，我们的研究为Aβ介导的NMDAR表达调控以及NMDARs在体感觉皮层Aβ病理生理中的作用提供了新的见解。
Onset and progression of Alzheimer’s disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aβ) toxicity. NMDAR expression, on the other hand, can be affected by Aβ. We tested whether the high vulnerability of neocortical neurons for Aβ-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aβ. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aβ-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aβ-overexpression. NMDARs were required for both Aβ-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aβ-mediated regulation of NMDAR expression and the role of NMDARs in Aβ pathophysiology in the somatosensory cortex.
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影响因子：
9.8
作者：
Dieterich, Daniela C.;Karpova, Anna;Mikhaylova, Marina;Zdobnova, Irina;Koenig, Imbritt;Landwehr, Marco;Kreutz, Martin;Smalla, Karl-Heinz;Richter, Karin;Landgraf, Peter;Reissner, Carsten;Boeckers, Tobias M.;Zuschratter, Werner;Spilker, Christina;Seidenbecher, Constanze I.;Garner, Craig C.;Gundelfinger, Eckart D.;Kreutz, Michael R.
通讯作者：
Kreutz, Michael R.
影响因子：
16.2
作者：
Berry KP;Nedivi E
通讯作者：
Nedivi E
CKAMP44调节侧向核核中视觉输入的整合。
影响因子：
16.6
作者：
Chen X;Aslam M;Gollisch T;Allen K;von Engelhardt J
通讯作者：
von Engelhardt J
影响因子：
16.2
作者：
Gray JA;Shi Y;Usui H;During MJ;Sakimura K;Nicoll RA
通讯作者：
Nicoll RA
影响因子：
4
作者：
Ferreira, I. L.;Bajouco, L. M.;Rego, A. C.
通讯作者：
Rego, A. C.