Abstract
Backgroundβ 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.MethodsWhole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ1–42 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.ResultsBlocking glutamate uptake with either TBOA or the human Aβ1–42 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 Aβ1–42-induced somatic potentiation and neuronal hyperactivity.ConclusionsThe 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.
Highlights
Neuronal hyperactivity is a major pathology commonly present in a number of neurological disorders, including Alzheimer’s disease (AD) [1,2,3]
Two minutes after TFB-threo-βbenzyloxyaspartic acid (TBOA) treatment, MK-801 (50 μM) was applied to the soma with pressure injection for 500 ms to block the activity of somatic N-methyl-D-aspartate receptors (NMDARs) (Fig. 4a). We found that this brief blockade of somatic NMDARs totally abolished the potentiation of evoked EPSPs (eEPSPs) elicited by TFB-TBOA treatment
Via pressure injection to the dendrite that is proximal to the site of electrical stimulation. We found that this brief blockade of NMDAR activity at the stimulated dendrite failed to exert any significant influence on the potentiation of the dendritic input
Summary
Neuronal hyperactivity is a major pathology commonly present in a number of neurological disorders, including Alzheimer’s disease (AD) [1,2,3]. Bao et al Transl Neurodegener (2021) 10:34 deficits in glutamate transporters (GLTs) in glial cells, which result in the accumulation of ambient glutamate in the extracellular milieu [5], leading to the activation of additional glutamate receptors (GluRs) and potentiating the tonic activation of GluRs on surrounding neurons. A recent study has demonstrated that local application of Aβ peptide to hippocampal CA1 neurons can mimic the effect of TBOA in inducing neuronal hyperactivity through initiating the suppression of glutamate reuptake [8] Despite these findings, how deficits in GLT reuptake in glial cells contribute to neuronal hyperactivity remains largely unknown
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