Characterization of Epileptic Spiking Associated With Brain Amyloidosis in APP/PS1 Mice

Abstract

Epileptic activity without visible convulsions is common in Alzheimer's disease (AD) and may contribute adversely to the disease progress and symptoms. Transgenic mice with amyloid plaque pathology also display epileptic seizures, but those are too infrequent to assess the effect of anti-epileptic treatments. Besides spontaneous seizures, these mice also display frequent epileptic spiking in epidural EEG recordings, and these have provided a means to test potential drug treatment to AD-related epilepsy. However, the origin of EEG spikes in transgenic AD model mice has remained elusive, which makes it difficult to relate electrophysiology with underlying pathology at the cellular and molecular level. Using multiple cortical and subcortical electrodes in freely moving APP/PS1 transgenic mice and their wild-type littermates, we identified several types of epileptic spikes among over 15 800 spikes visible with cortical screw electrodes based on their source localization. Cortical spikes associated with muscle twitches, cortico-hippocampal spikes, and spindle and fast-spindle associated spikes were present equally often in both APP/PS1 and wild-type mice, whereas pure cortical spikes were slightly more common in APP/PS1 mice. In contrast, spike-wave discharges, cortico-hippocampal spikes with after hyperpolarization and giant spikes were seen almost exclusively in APP/PS1 mice but only in a subset of them. Interestingly, different subtypes of spikes responded differently to anti-epileptic drugs ethosuximide and levetiracetam. From the translational point most relevant may be the giant spikes generated in the hippocampus that reached an amplitude up to ± 5 mV in the hippocampal channel. As in AD patients, they occurred exclusively during sleep. Further, we could demonstrate that a high number of giant spikes in APP/PS1 mice predicts seizures. These data show that by only adding a pair of hippocampal deep electrodes and EMG to routine cortical epidural screw electrodes and by taking into account underlying cortical oscillations, one can drastically refine the analysis of cortical spike data. This new approach provides a powerful tool to preclinical testing of potential new treatment options for AD related epilepsy.

Hippocampal alterations in glutamatergic signaling during amyloid progression in AβPP/PS1 mice

“…Hippocampal hyperactivity is observed in Aβ positive MCI patients, which persists with disease progression despite increasing rates of hippocampal atrophy and dementia scale ratings 9 . Elevated hippocampal activity has also been reported in several mouse models of AD with progressive amyloidosis 24 – 28 . These changes in neuronal networks are initially observed in mice before plaque deposition 29 , 30 , supporting a role for soluble Aβ in neuronal hyperactivity.…”

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

“…Several lines of evidence suggest that hyperexcitability is a contributing factor, primarily in familial AD (Chin and Scharfman, 2013; Friedman et al, 2012; Ghatak et al, 2019; Noebels, 2011; Nygaard et al, 2015; Palop et al, 2007; Palop and Mucke, 2009; Palop and Mucke, 2010; Petrache et al, 2019; Siskova et al, 2014; Styr and Slutsky, 2018; Verret et al, 2012; Vossel et al, 2013; Vossel et al, 2017). Hyperexcitability is manifested by intermittent seizures or epileptiform activity in an electroencephalogram (EEG) (Chin and Scharfman, 2013; Friedman et al, 2012; Gureviciene et al, 2019; Noebels, 2011; Nygaard et al, 2015; Palop et al, 2007; Palop and Mucke, 2009; Palop and Mucke, 2010; Verret et al, 2012; Vossel et al, 2013; Vossel et al, 2017). The seizures are easily missed because they are not always accompanied by movement, and epileptiform activity is easily missed because an EEG is not always conducted, or recordings are made far from the site of abnormal activity (Lam et al, 2019).…”

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs

“…No EEG study on AD patients to our knowledge has discovered SWDs, but so far only a couple of studies have more in detail described examples of any kind of nonconvulsive epileptic spiking in AD patients 2,52 . In contrast, two independent research groups have found substantial overrepresentation of SWDs in APP/PS1 mice compared wild-type littermates while the number of single cortical spikes did not differ between the genotypes 19,53 and a recent study reported an eightfold higher occurrence of SWDs in APP/PS1 transgenic rats than in wild-type littermates 54 . Together, these findings suggest that SWDs are closely linked to brain amyloidosis.…”