Abstracts

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. 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 agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). Following KA-SE in rats, KARs are expressed on reactive hippocampal astrocytes (Vargas et al, 2013) and may either protect against or increase susceptibility to epilepsy, yet little is known about astrocytic KARs in AD. We thus hypothesized that PSEN2 knockout (KO) mice would have reduced KA-SE latency, increased convulsive SE severity, worsened outcomes 7-days later, and altered hippocampal neuronal and astrocytic KAR expression vs matched WTs

Methods: Using a repeated low-dose systemic KA administration SE model, we quantified the latency to convulsive SE and extent of SE-induced neuropathology in 3–4-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, PSEN2 KO mice were more susceptible to KA-SE than WT mice. Male PSEN2 KO mice progressed to 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). GluK5 and GFAP expression did not differ between untreated sexes or genotypes. However, reactive gliosis and GluK5 expression was significantly greater in KA-SE WT versus sham-treated WT males 7-days post-KA-SE, (p< 0.0001, p=0.02). While reactive astrogliosis increased in PSEN2 KO mice following KA-SE (p=0.04), GluK5 levels were unchanged vs sham-treated PSEN2 KO mice (p >0.4). Astrogliosis increased following KA-SE only in female PSEN2 KO mice (p=0.02), whereas GFAP expression in WT mice was unchanged vs sham (p >0.1). Regardless of genotype, GluK5 expression in female mice was unchanged vs sham 7-days post-KA-SE, revealing notable sex differences. The effects of KA-SE on GluK2 and Ab expression will be further discussed.

Conclusions: Loss of normal PSEN2 function increases susceptibility to KA-induced seizures and SE, which cannot be explained by GluK5 expression differences or Ab. However, GluK5 expression was increased in male WT vs PSEN2 KO mice 7-days post KA-SE, implicating PSEN2 in KAR availability.


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