Abstracts

Neuronal hyperexcitability is being increasingly recognized as a critical factor in Alzheimer’s disease (AD) progression. Seizures are present in up to 20% of AD patients, often manifest prior to the onset of cognitive impairment, and are associated with accelerated clinical disease progression. Similarly, we have previously demonstrated that seizure induction exacerbates AD pathology and cognitive deficits in preclinical disease models. However, the effects of seizures on neuronal physiology in AD are underexplored. We hypothesized that seizure induction in prodromal amyloid precursor protein knock in (APP^NLGF/NLGF) mice would acutely worsen inhibitory function and that these changes will be long-lasting.

For these studies, we performed pentylenetetrazol (PTZ) seizure kindling or control, saline, protocols in 3-4 month old APP^NLGF/NLGF and age-matched WT mice. Whole cell patch clamp recording was performed in CA1 hippocampal neurons 24 hours and 2-3 months following seizure induction to assess intrinsic excitability and inhibitory synaptic function. For statistics, we used one-way ANOVA followed by Tukey’s multiple comparison to compare the four groups.

We found that APP^NLGF/NLGF mice require significantly less PTZ administrations to induce tonic-clonic seizures (p< 0.0001, n=19-24), consistent with our prior reports of increased seizure susceptibility in another AD mouse model carrying AD-linked mutations (5XFAD). Action potential (AP) firing rate in response to current injection remained unchanged at both 24 hours (n=3 mice/group, 15-16 cells/group) and 2-3 months (n=3 mice/group, 19-30 cells/group) following seizure induction. However, at 24 hours, we found reduced mini inhibitory post synaptic current (mIPSC) amplitude in both Sal and PTZ treated APP^NLGF/NLGF mice, as well as in PTZ kindled WT mice compared to WT/Sal (p< 0.0001, n=3 mice/group, 12-14 cells/group), and increased mIPSC intervals in PTZ kindled APP