Seizure susceptibility and hippocampal network hypersynchrony at a young age in a triple transgenic mouse model of Alzheimer’s disease

Alzheimer's disease (AD) patients are at an increased risk of developing seizures and epilepsy. Seizure incidence is higher in early-onset familial AD than in late-onset sporadic AD. The hypersynchronous network activity predisposing to seizures in AD may be primarily linked to AD pathology. However, it remains unclear if epileptiform activity precedes extensive disease pathology in AD and what are the underlying cellular mechanisms. Here, we evaluated seizure susceptibility and hippocampal network hypersynchrony at young age (prior to amyloid plaque deposition and neurofibrillary pathology) in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated amyloid-β precursor protein (AβPP), tau, and presenilin 1 genes. Experiments were performed in ∼3 week-old 3xTg-AD mice and wild type (WT) controls. In vivo epileptogenic susceptibility was tested by measuring incidence of seizures and death in animals subjected to auditory stimulation. Hypersynchronous network activity was evaluated by recording epileptiform discharges from CA3 pyramidal cells in in vitro hippocampal slices after blockade of GABAA receptor-mediated inhibition with bicuculline. The effects of the mGluR5 selective antagonist MPEP and of passive immunization with a human AβPP/Aβ antibody (6E10) on audiogenic seizure susceptibility and epileptiform discharges in transgenic mice were examined. Audiogenic stimulation elicited seizures in a higher proportion of 3xTg-AD mice compared with WT controls. Seizure susceptibility in 3xTg-AD mice was attenuated by either MPEP or passive immunization with 6E10. Bicuculline induced prolonged, ictal-like epileptiform discharges (>1.5 s in duration) in 80% of the hippocampal slices from 3xTg-AD mice; in contrast, only short, interictal-like discharges (<1.5 s) were observed following bicuculline application in WT slices. MPEP suppressed the prolonged epileptiform discharges in 3xTg-AD slices. The ictal-like activity in hippocampal slices of 3xTg-AD mice that were immunized with 6E10 was reduced compared to untreated 3xTg-AD mice: only 42% of the slices exhibited prolonged epileptiform discharges and their appearance following bicuculline was delayed. Our data suggest that (1) neuronal hyperexcitability underlying seizure susceptibility precedes extensive amyloid β and tau pathologies in a transgenic mouse model of familial AD, and (2) AβPP/Aβ and mGluR5 may play a role in network hypersynchrony in AD.