Loss of Presenilin 2 Increases Susceptibility to Kainate-Induced Acute Seizures in an Age-
Dependent Manner
Abstract number :
1.212
Submission category :
2. Translational Research / 2E. Other
Year :
2025
Submission ID :
789
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Larissa Robinson-Cooper, BS – University of Washington
Stephanie Davidson, BS – University of Washington
Kangni Zhang, BS – University of Washington
Hannah Park, BS – University of Washington
Melissa Barker-Haliski, PhD – University of Washington
Rationale: Presenilin 2 (PSEN2) gene variants increase the risk of early-onset Alzheimer’s disease (AD). AD patients with PSEN2 variants have increased risk of unprovoked seizures versus age-matched healthy controls, yet few studies have interrogated PSEN2 contributions to seizure susceptibility, and fewer have done so in aged models. PSEN2 variant mouse models also do not exhibit amyloid-b (Ab) plaques, allowing for the assessment of Ab -independent contributions to seizure risk in AD. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring KAR agonist that acutely evokes sustained, severe seizures in mice. We thus hypothesized that PSEN2 knockout (KO) mice would have reduced latency to acutely evoked seizures and status epilepticus (SE), increased convulsive SE severity, worsened survival 7-days later, and altered hippocampal KAR expression vs age-matched WTs.
Methods: Using a repeated low-dose systemic KA administration SE model, we quantified the latency to convulsive SE and extent of neuropathology in 3–4-month-old and 12–15-month-old male and female PSEN2 KO vs WT mice (n=10-16 mice/group/sex). GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham to define the impacts of PSEN2 loss and convulsive SE on hippocampal KAR expression and Ab accumulation.
Results: Regardless of sex, young PSEN2 KO mice were more susceptible to KA-induced acute seizures and SE than WT mice. Male PSEN2 KO mice entered SE faster than WTs (78.6±25.3 vs 98.2±16.0 min; t=2.43, p=0.03); female PSEN2 KO mice were also more susceptible to KA-SE relative to WTs (85.3±32.2 vs 112.2±15.4 min; t=2.447, p=0.02). In aged mice, there was no significant difference in latency to SE between genotypes in either sex. Only females showed an age-related decrease in latency to SE (WT (p< 0.0001); PSEN2 KO (p=0.001)). This was not observed in males. Among young animals there was no difference in KAR expression between genotypes and regardless of treatment group. However, in aged mice, there was a significant decrease in GluK5 expression in untreated PSEN2 KO mice versus untreated WT mice (p=0.01). While total GluK2 expression did not differ between genotypes or treatment groups, GluK2 colocalization with astrocytic markers only significantly increased in aged PSEN2 KO mice after KA-SE (p=0.001).
Conclusions: Loss of normal PSEN2 function exclusively increases susceptibility to KA-induced seizures and SE in young mice. Differences in susceptibility to KA-SE disappear with age suggesting that PSEN2 KO mice may promote accelerated senescence. Further, only females showed an age-related increase in susceptibility to KA-induced seizures and SE, highlighting sex differences that reproduce the greater clinical burden of AD in women. Further studies are needed to determine whether targeting astrocytic KARs may offer therapeutic benefit for seizures in late life, including in AD.
Funding: This work was supported by NIA R01AG067788 (MBH).
Translational Research