Abstracts

Rationale:
Both epilepsy and Alzheimer’s disease (AD) are defined by neuronal hyperexcitability and glutamate excitotoxicity. Presenilin 2 (PSEN2) gene variants increase early-onset AD risk and risk of unprovoked seizures vs age-matched unaffected individuals. Yet, few studies have determined the role of PSEN2 on seizure susceptibility and antiseizure medicine (ASM) efficacy. Genetic models of neuronal hyperexcitability are quite useful to probe novel therapeutic targets for epilepsy (Barker-Haliski & Hawkins, 2024). Clinically, AD-related PSEN2 variants evoke a biochemical loss of normal g-secretase function making PSEN2 knockout (KO) mice useful to a priori assess how loss of normal PSEN2 activity influences seizures and ASM efficacy. Young PSEN2 KO mice exhibit marked differences in ASM efficacy and potency vs wild-type (WT) mice in the acute 6 Hz seizure test (Lehmann & Barker-Haliski, 2023). PSENs may also be a novel regulator of presynaptic hippocampal kainate-type glutamate receptors (KARs); PSEN deletion can reduce KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is an agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized that PSEN2 KO mice would demonstrate differential sensitivity to conventional ASMs in response to KA-induced generalized seizures and SE.




Methods: Using a repeated low-dose KA-SE model, we quantified the latency to SE in 3–4-month-old male and female PSEN2 KO vs WT mice (n=10-17 mice/group/sex). Once behavioral SE onset was confirmed (two consecutive Racine stage 4+ seizures in 30 min), one of four ASMs were administered 15 min later to model clinical SE intervention protocols: all i.p., lorazepam (2 mg/kg); valproic acid (150 mg/kg); levetiracetam (300 mg/kg); topiramate (45 mg/kg). Protection from further convulsive SE was monitored for an additional 60 minutes and compared to outcomes of vehicle-treated mice. Mice recovered for 24-hours, and body weight was then recorded.

Results: Regardless of sex, 3–4-month-old PSEN2 KO mice had reduced latency to first Stage 4+ seizure but there was no difference in time from seizure onset to SE. The anticonvulsant efficacy of conventional ASMs was compared between PSEN2 KO and WT mice, with lorazepam, valproic, and levetiracetam conferring anticonvulsant efficacy across genotypes. Conversely, topiramate appears to have worsened SE in PSEN2 KO relative to VEH-treated PSEN2 KO mice. Specifically, seizure burden of PSEN2 KO males (11.0 +/- 15.5) mice was significantly increased in topiramate-treated male mice (31.0+/-18.9). In contrast, valproic acid and lorazepam suppressed convulsive SE. Further, PSEN2 KO male mice had worsened KA SE-induced 24-hour mortality vs WT (p=0.02); an effect not observed in females.

Conclusions: Young adult PSEN2 KO mice were more susceptible to KA-induced seizures and SE vs WT mice. Our study demonstrates that increased seizure susceptibility in this AD-associated mouse model may be well-suited to ASM screening, thereby expanding the potential to uncover novel therapeutic treatments for seizures in AD.

Funding: This work was supported by NIA R01AG067788 (MBH).