Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most severe consequence of uncontrolled epilepsy. SUDEP is a multifactorial outcome associated with serotonin (5-HT) imbalance and exacerbated neuroinflammation. Unfortunately, current preclinical models do not address all biological aspects of SUDEP. Seizures are a common comorbidity in Alzheimer’s disease (AD), especially in patients with variants in amyloid precursor protein (APP) and presenilin 1 (PSEN1) and 2 (PSEN2) genes. Clinical data suggests that seizures in AD patients increase mortality vs those without AD or unaffected controls. We have reported that corneal kindling of young APP/PSEN1 mice induces significant premature mortality, worsened neuroinflammation, and disrupted 5-HT system protein expression prior to AD pathology onset (Del Pozo et al, Prog Neurobiol 2024). Given this relationship, we hypothesized that kindled seizures in APP/PSEN1 mice could effectively screen preventative strategies for SUDEP, as well as uncover novel molecular changes related to hyperexcitability.

Methods: Young (2-month-old) male and female APP/PSEN1 mice underwent 60 Hz corneal kindling and were treated prior to each evoked stimulation with lorcaserin (LORC; 10 mg/kg, i.p), a selective 5-HT receptor agonist, or cannabidiol (CBD; 100 mg/kg), a broad-spectrum anti-inflammatory and 5-HT modulator. Kindling acquisition and survival was tracked for 3 weeks. Terminal analysis of isolated hippocampus quantified chronic seizure-induced changes in neuroinflammation, 5-HT system enzyme expression, and GABAergic neuron density.

Results: Corneal kindling of APP/PS1 mice significantly increased premature mortality, regardless of biological sex, which was prevented by repeated LORC administration to male and female APP/PS1 mice (X²=7.30, p=0.007 in males; X²=4.27, p=0.004 in females). Corneal kindling of APP/PS1 mice significantly increased soluble amyloid-b protein expression, which was not evident in mice repeatedly treated with CBD or LORC. CBD and LORC treatment significantly reduced TLR4 expression in isolated hippocampus of corneal kindled APP/PS1 mice (p< 0.001). Corneal kindling of APP/PS1 mice significantly altered expression of 5-HT pathway proteins, yet repeated administration of CBD and LORC did not significantly modify this expression in kindled APP/PS1 mice (*p< 0.05). Finally, kindled wild-type littermates showed increased GAD65/67 levels in hippocampal CA1, which was absent in kindled APP/PS1 mice (F