Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance.
Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance.
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可溶性 Aβ 寡聚物通过破坏谷氨酸能/GABA 能平衡来损害海马 LTP
DOI：
10.1016/j.nbd.2015.10.019
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发表时间：
2016-01
影响因子：
6.1
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Lei M;Xu H;Li Z;Wang Z;O'Malley TT;Zhang D;Walsh DM;Xu P;Selkoe DJ;Li S
癫痫活动在早期阿尔茨海默病（AD）中可能比以前认为的更普遍。几项研究报告了发生年龄相关Aβ蓄积的AD小鼠模型中的自发性癫痫发作和发作间期放电。Aβ诱导的神经元兴奋性触发癫痫样活动的机制仍不清楚。在这里，我们系统地研究了场兴奋性突触后电位在放射层和人口尖峰在相邻层的CA 1野生型小鼠海马脑片。可溶性Aβ寡聚体（oAβ）阻断海马LTP和EPSP-峰电位（E-S）增强，这些作用可通过预先给予谷氨酸摄取抑制剂TBOA阻断。与此雅阁，oAβ升高了海马切片培养基中的谷氨酸水平。记录群体峰电位（PS）显示，oAβ增加PS频率和减少LTP，后者的作用被GABAA拮抗剂印防己毒素阻断。全细胞记录显示oAβ显著增加自发EPSC频率。通过增加GABA张力或部分阻断NMDAR活性来降低神经元活性可防止海马LTP的oAβ损伤。最后，用两种抗癫痫药物处理脑片可解除oAβ诱导的LTP抑制。我们得出结论，AD脑中存在的低纳摩尔水平的可溶性Aβ寡聚体通过破坏谷氨酸能/GABA能平衡增加神经元兴奋性，从而损害突触可塑性。
Epileptic activity may be more prevalent in early stage Alzheimer’s disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials in stratum radiatum and population spikes in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording population spikes (PS) revealed that oAβ increased PS frequency and reduced LTP, and the latter effect was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.