NMDAR-dependent somatic potentiation of synaptic inputs is correlated withβamyloid-mediated neuronal hyperactivity  

作　　者：Yifei Bao Xin Yang Yi Fu Zhengyan Li Ru Gong Wei Lu 

机构地区：[1]MOE Key Laboratory of Developmental Genes and Human Disease,School of Life Science and Technology,Southeast University,Nanjing 210096,China [2]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 [3]Co-Innovation Center of Neuroregeneration,Nantong University,Nantong 226001,China

出　　处：《Translational Neurodegeneration》2021年第3期432-446,共15页转化神经变性病（英文）

基　　金：This work was supported by grants to W.L.from the National Natural Science Foundation of China(31730107,31970959,31671056).

摘　　要：Background:βAmyloid(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 difuse 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.Methods: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_(1-42) peptide oligomer.A series of dendritic patch-clamp recordings were made at diferent 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.Results:Blocking glutamate uptake with either TBOA or the human Aβ_(1-42) peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons.Strikingly,this potentiation specifcally 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_(1-42)-induced somatic potentiation and neuronal hyperactivity.Conclusions:The somatic potentiation of synaptic inputs may represent a novel amplifcation mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.

关 键 词：NMDA receptor HYPERACTIVITY Somatic modifcation Alzheimer’s disease 

分 类 号：R338[医药卫生—人体生理学]