NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity

Yifei Bao; Xin Yang; Yi Fu; Zhengyan Li; Ru Gong; Wei Lu

doi:10.1186/s40035-021-00260-3

NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity

Transl Neurodegener. 2021 Sep 8;10(1):34. doi: 10.1186/s40035-021-00260-3.

Authors

Yifei Bao^#¹, Xin Yang^#¹, Yi Fu¹, Zhengyan Li¹, Ru Gong¹, Wei Lu^{2

3

4}

Affiliations

¹ MOE Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, 210096, China.
² MOE Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, 210096, China. luwei@seu.edu.cn.
³ 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. luwei@seu.edu.cn.
⁴ Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. luwei@seu.edu.cn.

^# Contributed equally.

Abstract

Background: 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.

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 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.

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 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 Aβ_1-42-induced somatic potentiation and neuronal hyperactivity.

Conclusions: 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.

Keywords: Alzheimer’s disease; Hyperactivity; NMDA receptor; Somatic modification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / toxicity*
Animals
Aspartic Acid / toxicity
Cell Body / drug effects
Cell Body / physiology*
Excitatory Postsynaptic Potentials / drug effects
Excitatory Postsynaptic Potentials / physiology*
Humans
Male
Neurons / drug effects
Neurons / physiology*
Organ Culture Techniques
Peptide Fragments / toxicity*
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / physiology*
Synapses / drug effects
Synapses / physiology*

Substances

Amyloid beta-Peptides
Peptide Fragments
Receptors, N-Methyl-D-Aspartate
amyloid beta-protein (1-42)
benzyloxyaspartate
Aspartic Acid