Authors :
Presenting Author: Stephanie Davidson, BS – University of Washington
Larissa Robinson-Cooper, BS – Graduate Student, Center for Epilepsy Drug Discovery (CEDD), Department of Pharmacy; Graduate Program in Neuroscience, University of Washington; Rami Koutoubi, in progress – Undergraduate Student Researcher, Center for Epilepsy Drug Discovery (CEDD), Department of Pharmacy, University of Washington; Melissa Barker-Haliski, PhD – Research Associate Professor, Center for Epilepsy Drug Discovery (CEDD), Department of Pharmacy, University of Washington
Rationale: Both epilepsy and Alzheimer’s disease (AD) are defined by glutamate excitotoxicity-evoked neuropathology. Three deterministic risk genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) increase the risk of early-onset AD. People with these gene variants are also at greater risk of unprovoked seizures than age-matched non-affected individuals. However, most studies assessing the pathological link between epilepsy and AD have focused on APP and PSEN1 variants. Few studies have interrogated the contributions of PSEN2 on seizure susceptibility even though patients with PSEN2 variants experience seizures as frequently as people with APP duplications. PSEN2 variants lead to a biochemical loss of normal γ-secretase function making PSEN2 knockout (KO) mice useful to
a priori assess how loss of normal PSEN2 proteolytic processing influences seizures and resulting pathology. We have previously reported that young PSEN2 KO mice are less susceptible to corneal kindling, a model of acquired temporal lobe epilepsy, than age-matched wild-type (WT) mice (Beckman et al, 2020; Knox et al 2023). Critically, PSEN proteolytic capacity may be a novel regulator of presynaptic 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). We thus hypothesized PSEN2 KO mice would exhibit reduced KA-induced SE latency, increased SE severity, and worsened outcomes seven days later.
Methods: Using a repeated low-dose KA-SE model, we quantified the latency to SE and SE-induced neuropathology in three to four month old male and female PSEN2 KO relative to WT mice (n=10-16 mice/group/sex). KAR expression was colocalized in astrocytes and neurons by immunohistochemistry seven days after KA SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression.
Results: Regardless of sex, three to four month old PSEN2 KO mice had reduced latency to first Stage 4/5 seizure and SE onset, in contrast to our earlier findings of delayed kindling acquisition at this age. Male PSEN2 KO mice took 61.3±23.5 versus 87.6±15.5 min in WT mice to present with an initial stage 4/5 seizure after KA injections (t=3.30, p=0.0028); female PSEN2 KO mice took 67.2±32.9 versus 102.7±16.9 min in WT mice (t=3.13, p=0.0047). Similarly, male PSEN2 KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t=2.43, p=0.027); female PSEN2 KO mice were also more susceptible to KA SE relative to WTs (85.3±32.2 versus 112.2±15.4 min). PSEN2 KO male mice had worsened KA SE-induced 24-hour mortality versus WT (p=0.0237); an effect not similarly observed in females. The immunohistopathological impact of KA SE in PSEN2 KO versus WT mice will be further discussed.
Conclusions:
Loss of normal PSEN2 function increases susceptibility to KA-induced seizures and SE. Our study builds on earlier work indicating that PSENs may critically mediate normal hippocampal KAR expression and function, which may influence seizure susceptibility in AD.
Funding: This work was supported by NIA R01AG067788 (MBH).