Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.
Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.
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DOI：
10.1111/acel.13455
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发表时间：
2021-09
期刊：
影响因子：
7.8
通讯作者：
Aguayo LG
中科院分区：
文献类型：
--
作者：
Fernandez-Perez EJ;Muñoz B;Bascuñan DA;Peters C;Riffo-Lepe NO;Espinoza MP;Morgan PJ;Filippi C;Bourboulou R;Sengupta U;Kayed R;Epsztein J;Aguayo LG
细胞内淀粉样β寡聚体(IAβo)蓄积和神经元过度兴奋性是阿尔茨海默病(AD)早期的两个重要事件。然而，到目前为止，还没有关于IAβo与神经元兴奋性增加有关的机制的报道。本实验观察了人AD脑源性多肽(h-IAβo)和人工合成多肽(IAβo)对海马神经元突触电流和动作电位放电的影响。从下午500时开始，IAβo迅速增加突触电流的频率，较高的浓度增强了AMPA受体介导的电流。这两种作用都依赖于PKC。突触电流和一氧化氮(NO)相关荧光的平行记录表明，与突触前释放有关的频率增加依赖于NO介导的逆行信号。此外，在用IAβo透析的邻近神经元中，也观察到NO产生的同步性增加，这表明IAβo可以增加网络的远距离兴奋性。电流钳记录显示，IAβo通过AMPA驱动的突触活动增加神经元的兴奋性，而不改变膜的固有特性。这些结果有力地表明，IAβo通过突触驱动机制导致超兴奋性的功能性传播，并对AD早期的细胞内物种具有重要的神经病理学意义，包括脑高兴奋性和癫痫发作。在IAβo存在的情况下，PKC被激活(A)，进而允许在突触后水平产生一氧化氮(NO)，增加神经递质的释放(B)(证据是MPSC频率的增加)。PKC还增加AMPA受体电流(C)，增加突触后去极化和神经元兴奋性(D)。最后，IAβo可增加不含IAβo(E)的邻近神经元中同步化NO的产生。
Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain‐derived (h‐iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor‐mediated current. Both effects were PKC‐dependent. Parallel recordings of synaptic currents and nitric oxide (NO)‐associated fluorescence showed that the increased frequency, related to pre‐synaptic release, was dependent on a NO‐mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current‐clamp recordings suggested that iAβo increased neuronal excitability via AMPA‐driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic‐driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures. In the presence of iAβo, PKC is activated (a), which in turn allows the production of nitric oxide (NO) at the post‐synaptic level, increasing the release of neurotransmitters (b) (evidenced as an increase in the frequency of mPSC). PKC also increases AMPA receptor current (c), increasing post‐synaptic depolarization and neuronal excitability (d). Finally, iAβo increases synchronization NO production in nearby neurons that do not have iAβo (e).
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影响因子：
3.7
作者：
Davis KE;Fox S;Gigg J
通讯作者：
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影响因子：
64.5
作者：
Arancio, O;Kiebler, M;Hawkins, RD
通讯作者：
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DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
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通讯作者：
Konnerth, Arthur
影响因子：
5.3
作者：
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通讯作者：
Jankowsky, Joanna L.
DOI：
10.1016/j.bbrc.2005.10.169
发表时间：
2005-12-30
影响因子：
3.1
作者：
Chen, C
通讯作者：
Chen, C