Presenilin 2 Knockout Mice are More Sensitive to Acute Valproic Acid in the 6 Hz Model of Focal Seizures

Patients with Alzheimer’s disease (AD) experience undetected focal seizures, which could worsen overall disease burden (e.g., accelerate cognitive decline and worsen neuropsychiatric comorbidities). Genetic variants in presenilin 2 (PSEN2) are associated with early‐onset AD and result in a loss of normal PSEN2 function, which forms the catalytic component of the g‐secretase enzyme. These patients also experience seizures (Jayadev et al, Brain 2010). Nonetheless, seizures in PSEN2 variant mouse models of AD are significantly understudied (Lehmann et al, Neurochem Res 2021); most prior preclinical work assessing seizure susceptibility and antiseizure drug (ASD) efficacy has been conducted in amyloid precursor protein‐overexpressing models. There are over 30 approved ASDs that may be effective in controlling seizures in AD. However, ASD efficacy and tolerability is not routinely assessed in aged rodent seizure models, nor in models with AD‐associated genotypes. This project thus aimed to establish the dose‐dependent anticonvulsant efficacy of ASDs in the mouse 6 Hz model of focal seizures evoked in PSEN2 knockout (KO) mice.