Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.

UNLABELLED

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 seizures, and fewer have done so with aging. PSEN2 variant mice also do not exhibit amyloid-β (Aβ) accumulation, allowing for the assessment of Aβ-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 (Barthet et al 2022). Kainic acid (KA) is a naturally occurring KAR agonist that acutely evokes 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 burden, worsened 7-day survival, and altered hippocampal KAR expression vs age-matched wild-type (WT) mice. Using a repeated low-dose systemic KA administration paradigm, we quantified the latency to acute seizures and convulsive SE, then quantified neuropathology in 3-4-month-old and 12-15-month-old male and female PSEN2 KO versus WT mice. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham-SE to define the interaction between PSEN2 loss and acute seizures on hippocampal KARs. Regardless of sex, young PSEN2 KO mice were more susceptible to KA-induced acute seizures than WTs. Young PSEN2 KO mice of both sexes also entered SE sooner than age-matched WT mice. In aged mice, there was no significant difference in latency to first seizure or SE onset between genotypes in either sex. However, regardless of genotype, aged females entered SE sooner than young females and experienced greater mortality. This was not observed in males. Among young animals, there was no difference in KAR expression between genotypes and regardless of treatment group. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 following KA-SE, however, astrocytic GluK2 expression only occurred in WT mice. GluK5 expression was significantly reduced in untreated aged PSEN2 KO mice versus untreated WT mice, while total GluK2 expression did not differ between genotypes or seizure groups. Following KA-SE, astrocytic GluK5 expression was only present in WT animals in CA3, while both genotypes presented with astrocytic GluK5 expression. This study highlights that KARs are an understudied contributor to seizures in aging and AD that warrant further investigation.

HIGHLIGHTS

• Alzheimer's disease (AD) and epilepsy share many pathophysiological links, but the contributions of distinct AD-risk factors are understudied.- Aging also evokes long-term neurophysiological adaptations without hippocampal damage, which may be further worsened by acute seizures.- Loss of normal presenilin 2 function is associated with AD; its contributions to seizure risk across the lifespan have been minimally evaluated.- Loss of presenilin 2 increases susceptibility to kainic-acid induced acute seizures in young adult mice, mirroring susceptibility in late life.- Kainate receptor expression in older mice is only changed with loss of presenilin 2 function.