Abstracts

Rationale:
Early-onset Alzheimer’s disease (AD) is associated with variants in presenilin 2 (PSEN2), presenilin 1 (PSEN1), and amyloid precursor protein (APP). Patients with early-onset AD who express APP duplications or PSEN2 variants are at a significantly elevated risk of developing seizures. For example, 31.2% of patients with APP duplications and 28.6% of patients with PSEN2 variants experienced at least one seizure within 5 years of AD diagnosis (Zarea et al, Neurology 2016). We have established that corneal kindling of mice with loss of normal PSEN2 function (PSEN2 knockout) demonstrate age-related delays in corneal kindling (Beckman et al, Neurobiol Dis 2020). PSEN2 is a particularly attractive candidate to explore susceptibility to chronic seizures because PSEN2 variant models do not demonstrate accumulated amyloid-beta (Aβ), in contrast to APP-overexpressing mouse models. PSEN2-N141I is the most common PSEN2 gene variant associated with early-onset AD; patients with this variant are known to experience seizures (Jayadev et al, Brain 2010). We sought to establish whether transgenic expression of this AD-associated variant in mice altered the rate of kindling acquisition vs the rate of a common line of mice that overexpress APP (APPSWE/PS1dE9).
Method:
Male PSEN2-N141I and age-matched non-transgenic wild-type (WT-Tg) C57Bl/6J mice, and Male APP/PS1 and wild-type littermates (WT) C57Bl/6J, were corneal kindled with a 3 sec 60 Hz 1.6-3 mA current to kindling criterion (5 consecutive Racine stage 5 seizures) at 2-months-old. The duration of the kindled behavioral seizure was recorded 7-days post-kindling acquisition to define the kindled seizure severity in mice with and without these AD-associated genetic risk factors. The exploratory behavior of fully kindled mice was also then assessed 10 days post-kindling criterion in a non-habituated open field to quantify the potential for chronic seizure-induced changes in anxiety-like behaviors and spatial working memory deficits.
Results:
The rate of corneal kindling acquisition was significantly affected by AD genotype. Specifically, male APP/PS1 mice (n=5) took fewer (17.0±1.98) stimulations to attain the fully kindled state vs WT littermates (n=9; 21.2±0.91 stimulations, p< 0.05). Conversely, PSEN2-N141I mice took significantly more stimulations (n=13; 21.2±0.91) vs WT-Tg mice (n=11; 17.5±0.49; p< 0.01). Further, APP/PS1 mice demonstrated kindled seizures of significantly greater duration than WT littermates. The fully kindled seizure in APP/PS1 mice lasted on average 81.4±10.8 sec versus 40.6±1.58 sec of WT (p< 0.01). Conversely, the kindled seizure duration of 2-month-old PSEN2-N141I mice (50.6±3.16 sec) was no different from WT-Tg mice (51.4±2.99 sec). The activity of fully kindled mice in the open field will then be further discussed.