Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

Abstract

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.

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…The soluble forms of Aβ 1–42 peptide are pathological species present in AD that are widely used to investigate their contribution to the pathogenesis and progression of the disease (Selkoe & Hardy, ). In vitro acute application of Aβ 1–42 causes hippocampal hyperexcitability (Tamagnini et al, ; Varga et al, ) and deficits in LTP (Eslami et al, ; Kimura et al, ; Lei, Xu, & Li, ). Similarly, different in vivo experiments show that the administration of Aβ 1–42 triggers behavioral deficits because of alterations in neural excitability and LTP process (Kalweit et al, ; Sanchez‐Rodriguez et al, , ).…”

High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

“…Knowledge of this structural ensemble is interesting not only to design inhibitors, 72,73 but also to understand the interactions with many cellular partners in early stage Alzheimer’s disease. 4,74–77 …”

Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats

“…Aberrant neural activity is directly implicated in amyloid beta processing and release in neural circuitry affected early and severely in the course of AD (53), and the magnitude of amyloid deposition in key DMN hubs is coupled with changes in cortical rsdynamics (54). Recent evidence also indicates that soluble amyloid beta oligomer delivery both increases neuronal activity and blunts memory-related synaptic plasticity in the hippocampus (i.e., longterm potentiation), and that these effects are reversed by pharmacological treatments that restore normal neuronal excitability (55). Taken together, these findings raise the possibility that the changes in FC documented here may comprise neural network consequences of distributed changes in excitatory/inhibitory balance, and a signature of the neurobiological condition that renders cognitive aging the primary risk for neurodegenerative disease.…”