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

Abstract

AbstractBackgroundPatients 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.MethodMale and female PSEN2 KO and WT C57Bl/6 mice aged 3‐4 months were used to determine the median effective dose (ED50) of prototype ASDs (including valproic acid and carbamazepine). ASDs were acutely administered to assess dose‐related seizure control in the 6 Hz test based on our published methods (Koneval et al, Epilepsia 2020).ResultThe ED50 of valproic acid (VPA) in male PSEN2 KO mice was 62.7 mg/kg [48.6‐90.8]; significantly lower than the VPA ED50 for age‐matched male WT mice (158 mg/kg [108‐242]). In females, the VPA ED50 for PSEN2 KO mice was 93.3 mg/kg [39‐159], while in age‐matched WT female mice it was 163 mg/kg [120‐235]. Notably, the ED50 of carbamazepine (CBZ) in male PSEN2 KO mice (14.5 mg/kg [2.23 ‐ 23.6]) was not substantially different from WT mice.ConclusionPSEN2 KO mice may be more sensitive to acute administration of VPA than WT mice in the 6 Hz focal seizures model, but this sensitivity is not universal to all ASDs. This study demonstrates that loss of normal PSEN2 function may selectively increase the potency of clinically‐approved ASDs in this preclinical model of focal seizures.