Recent studies have indicated that some patients with Alzheimer’s disease (AD) experience undetected focal seizures, which could contribute to and/or worsen overall disease burden (e.g. cognitive function and neuropsychiatric comorbidities). Genetic variants in presenilin 2 (PSEN2) are associated with early-onset AD and result in a loss of normal PSEN2 function. Patients with PSEN2 mutations also experience seizures more frequently than age-matched individuals without AD. There are over 30 clinically approved antiseizure drugs (ASDs), which have been proposed to be effective in controlling these seizures, and thus reducing disease burden. ASD efficacy and tolerability is not, however, frequently determined in aged rodent seizure models nor in rodent models with AD-associated genotypes. This project thus aimed to establish the dose-dependent efficacy of mechanistically-distinct approved ASDs in the well-established mouse 6 Hz model of focal seizures, using both female and male PSEN2 knockout (KO) mice. Seizure susceptibility in PSEN2 variant mouse models of AD is generally understudied; most work previously has been conducted in amyloid precursor protein-overexpressing models. We thus first quantified the median convulsant current (CC50) in the 6 Hz model of focal seizures with male and female PSEN2 KO mice aged 3-4 months. The CC50 of female PSEN2 KO mice was 34.4 mA [95% confidence intervals 30.4-38.5]; in males it was 41.9 mA [39.3-46.9]. Candidate ASDs (valproic acid, lamotrigine, carbamazepine, levetiracetam, and perampanel) were then administered via intraperitoneal (IP) injection in a dose-related manner to assess dose-related seizure control in the 6 Hz test. Preliminary results indicate that PSEN2 KO mice may be more sensitive to administration of valproic acid than wild-type mice. This study is definitively addressing whether loss of normal PSEN2 function promotes any overt changes in the anticonvulsant efficacy of clinically-approved ASDs to better inform management of focal seizures in patients with AD.

Epilepsy is one of the most significant neurological diseases in the world. Although there have been numerous advances in the study of epilepsy, there is still much we can learn about it. This is supported by the fact that one third of the patients with epilepsy are resistant to their anti-seizure drugs. With the mechanisms of pharmacoresistant seizures still unresolved, this project utilizes the mouse 6 Hz model of pharmacoresistant focal seizures to help answer some of its questions. Specifically, we hypothesize that the extent of brain region activation is directly correlated with increasing stimulation intensity used to invoke a seizure. Using cFOS, a marker for neuronal activity, we characterized the effect of varying stimulation intensities on cFOS immunoreactivity and its recruitment of nearby brain regions at various stimulus intensities. Using the established 6 Hz model we determined the convulsive current that caused a seizure in 97% of the population (CC97) in adult male mice. Ninety minutes after stimulation, brains were extracted, and processed for immunohistochemical labeling of the early activation gene, cFOS. Pending results will determine whether increasing stimulation intensity will result in greater cFOS labelling as well as greater recruitment of surrounding brain regions. These data will inform our future studies investigating the effects of several antiseizure drugs on blocking the recruitment and activity of different brain regions at varying stimulus intensities in the 6 Hz model.