Soluble A beta oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance

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 A beta accumulation. The mechanism by which A beta-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble A beta oligomers (oA beta) blocked hippocampal LW and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oA beta elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oA beta increased PS frequency and reduced LW, and this LW deficit was occluded by pretreatment with the GABA(A) antagonist picrotoxin. Whole-cell recordings showed that oA beta significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oA beta impairment of hippocampal LW. Finally, treating slices with two antiepileptic drugs rescued the LW inhibition induced by oA beta. We conclude that soluble A beta oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity. (C) 2015 Elsevier Inc. All rights reserved.