3xTg Alzheimer’s disease mice are more susceptible to induced seizures

Abstract

AbstractBackgroundEpilepsy is a frequent comorbidity in patients with Alzheimer’s disease (AD).1 Early cellular hyperexcitability and seizures are present in several AD mouse models.2,3 The mechanisms responsible for these changes in excitability, the impact on the disease and how they could be reversed remain largely unknown.MethodWe used the triple‐transgenic (3xTg) mouse model, that has mutations affecting the two main proteins involved in AD: amyloid and tau. Seven‐week‐old female 3xTg (n = 19) and age‐ and gender‐matched wild‐type (n = 19) mice were corneally kindled with the 6 Hz electrical stimulations.4 Corneal kindling is a model of repeated induced seizures, where identical electric stimuli applied to the eyes, give rise to a progressive seizure phenotype. Once a mouse was fully kindled (defined as 10 consecutive generalized seizures), it was treated with several antiseizures drugs (ASDs) to assess their effect. Spontaneous locomotor activity and anxiety‐like behavior was tested with open field. After the experiments, mice were killed and brains were evaluated for amyloid and tau pathology with (immuno)histochemistry.ResultWhen subjected to identical stimuli 3xTg mice exhibit more severe seizures compared to wild‐type mice (p < 0.001). This difference is most prominent in the beginning of the kindling process and reduces over time (p < 0.001). Levetiracam and brivaracetam have similar efficacy in reducing seizure severity, lamotrigine is less effective. Seizures in 3xTg mice are more resistant to the three tested ASDs in comparison to wild‐type mice (p < 0.01). Despite being more active during handling after several weeks of corneal kindling, no increased spontaneous locomotor activity nor anxiety‐like behavior was detected in 3xTg mice.ConclusionThe presence of alterations in both amyloid and tau pathways results in an increase in seizure susceptibility at young age, before neurofibrillary tangles or amyloid plaques are expected to be present. The seizures of the 3xTg mice are more resistant to clinically used ASDs. The 6 Hz corneal kindling in mice is increasingly established as a model of epileptogenesis and an accessible model to assess seizure susceptibility and ASD effect in fully kindled AD mice.