Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy

Lisgaras, Christos Panagiotis; Oliva, Azahara; McKenzie, Sam; LaFrancois, John; Siegelbaum, Steven A.; Scharfman, Helen E.

doi:10.1101/2023.01.15.524149

Cited by 6 publications

(6 citation statements)

References 51 publications

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“…In epileptic mice, it has been reported that an increased occurrence of HFOs correlated to impaired memory 32 and that HFO disruption improves memory. 26 Thus, it is likely that the increased number of HFOs we found may affect memory performance at least in PS2KO and Ts65Dn mice that IIS appear to be infrequent. However, it is important to also consider that IIS alone have detrimental effects on memory.…”

Section: Discussionmentioning

confidence: 84%

“…IIS and HFOs were detected using the same criteria as described in our previous studies. 12,13,16,26,27 We quantified IIS or HFOs that occurred during periods of wakefulness, SWS, or REM; these behavioral states were defined as before. 12,16 IIS were included if their amplitude exceeded the mean of the baseline noise by more than 5 standard deviations.…”

Section: Methodsmentioning

confidence: 99%

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High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease

Lisgaras,

Scharfman

2023

Preprint

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Interictal spikes (IIS) and seizures are well-documented in Alzheimer’s disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state.We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep.In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS.In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS.SHORT SUMMARYInterictal spikes (IIS) and seizures are common in Alzheimer’s disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.

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Section: Discussionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease

Lisgaras,

Scharfman

2023

Preprint

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“…Preliminary results indicate that both chemogenetic and optogenetic inhibition of CA2 pyramidal neurons reduce seizures in chronically epileptic mice [65]. According to a recent study, the contralateral hippocampus could be involved in seizure generation providing another potential target for LFS.…”

Section: Discussionmentioning

confidence: 94%

“…In future studies, it would be informative to apply LFS to CA2 neurons in the seizure focus since these cells survive SE well in ihKA mice [37] and MTLE patients [64]. Preliminary results indicate that both chemogenetic and optogenetic inhibition of CA2 pyramidal neurons reduce seizures in chronically epileptic mice [65]. According to a recent study, the contralateral hippocampus could be involved in seizure generation providing another potential target for LFS.…”

Section: Discussionmentioning

confidence: 99%

Low frequency stimulation for seizure suppression: identification of optimal targets in the entorhinal-hippocampal circuit

Kleis,

Paschen,

Häussler

et al. 2024

Preprint

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BackgroundMesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low-frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE.Objective/HypothesisOur previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus.MethodsWe utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using Channelrhodopsin2 (ChR2) and stereotactic optic fiber implantation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to three hours.ResultsWe found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts.ConclusionPresynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS.

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“…IIS were detected using the same criteria as described in our previous studies. 11,14,53 In brief, we included IIS that exceeded the mean baseline by more than 5 standard deviations (SDs) during the same behavioral state.…”

Section: Iis Detection and Iis Amplitude Analysismentioning

confidence: 99%

Interictal Spikes in Alzheimer’s Disease: Preclinical Evidence for Dominance of the Dentate Gyrus and Cholinergic Control by Medial Septum

Lisgaras

Scharfman

2023

Preprint

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Interictal spikes (IIS) are a common type of abnormal electrical activity in animal models of Alzheimer′s disease (AD) and AD patients. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked where IIS are largest along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the medial septohippocampal cholinergic neurons selectively would reduce IIS. We used 3 models of AD, Tg2576 mice, presenilin 2 knockout mice, and the Ts65Dn mouse model of Down′s syndrome. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with ChAT-Cre mice and offspring mice were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs. We recorded EEG along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and were primarily during REM sleep. In all 3 models, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS frequency during REM sleep without affecting the overall duration or number of REM sleep bouts. Maximal IIS amplitude in the DG of 3 AD mouse models suggests that the DG could be one of the areas that contribute to IIS generation. Selectively reducing MS cholinergic tone could be a new strategy to reduce IIS in AD.

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Hippocampal area CA2 controls seizure dynamics, interictal EEG abnormalities and social comorbidity in mouse models of temporal lobe epilepsy

Cited by 6 publications

References 51 publications

High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease

High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease

Low frequency stimulation for seizure suppression: identification of optimal targets in the entorhinal-hippocampal circuit

Interictal Spikes in Alzheimer’s Disease: Preclinical Evidence for Dominance of the Dentate Gyrus and Cholinergic Control by Medial Septum

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