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

Alcantara‐Gonzalez, David; Chartampila, Elissavet; Criscuolo, Chiara; Scharfman, Helen E.

doi:10.1016/j.nbd.2021.105274

Cited by 23 publications

(24 citation statements)

References 161 publications

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“…Kv7/KCNQ/I M channels(Alcantara-Gonzalez et al, 2021), our data support a role for altered HCN/I h activity at early non-symptomatic stages of AD, as shown by lower I h responses and decreased HCN1 protein levels in hippocampal CA1. Of note, these changes are not paralleled by modifications of HCN1 mRNA levels, indicating that APP/Aβ overexpression does not alter transcription or stability of J o u r n a l P r e -p r o o f…”

supporting

confidence: 81%

Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer's disease mouse model

Rizzello¹,

Pimpinella²,

Pignataro³

et al. 2023

Neurobiology of Disease

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supporting

confidence: 81%

Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer's disease mouse model

Rizzello¹,

Pimpinella²,

Pignataro³

et al. 2023

Neurobiology of Disease

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“…19 Tg2576 transgenic mice develop memory deficits 20 and amyloid beta (Aβ) deposits by 6 months and robust plaque pathology by 12 months of age. 19,21 In addition, Tg2576 mice show IISs and seizures, 20 which allowed us to determine if HFOs coincide with them. Tg2576 transgenic mice were 5.5 ± 2.4 months of age (range 1-19 months) at the time of recording, when IISs and seizures are intermittent.…”

Section: Animalsmentioning

confidence: 99%

“…Instead, gap junctions, 42 intrinsic properties, and ion channels 43 have been suggested to contribute, and there are other possibilities. In AD models, altered intrinsic properties 21 and ion channels 16,44 have been identified already, which may contribute to HFOs.…”

Section: Similarities To Epileptic Animalsmentioning

confidence: 99%

High‐frequency oscillations (250–500 Hz) in animal models of Alzheimer's disease and two animal models of epilepsy

Lisgaras

Scharfman

2022

Epilepsia

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Objective To test the hypothesis that high‐frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy. Methods Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock‐out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1–500 Hz, 2 kHz) intra‐hippocampal and cortical surface electroencephalography (EEG) at 1 month until 24 months of age during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. In addition, interictal spikes (IISs) and seizures were analyzed for the possible presence of HFOs. Comparisons were made to the intra‐hippocampal kainic acid and pilocarpine models of epilepsy. Results We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1 month of age and prior to amyloid beta plaque neuropathology. HFOs were most frequent during SWS (vs REM sleep or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IISs and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. Significance Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker, which is detectable from the scalp and thus amenable to noninvasive detection in people at risk for AD.

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“…76 This idea is consistent with many observations of altered excitability in the DG in AD 25 or AD mouse models. 8,[71][72][73] Indeed, this view is also strengthened by our previous study showing that the DG is an early contributor to increased hippocampal excitability as shown by the occurrence of DG HFOs in vivo. 14 In addition, our findings pointing to the MS as a contributor to IIS activity is topical considering the urgent need for a better understanding of the role of subcortical structures in AD pathophysiology.…”

Section: Discussionmentioning

confidence: 57%

“…In vitro, slices of Tg2576 mice at 2-3 months of age showed increased excitability of GCs. 73 In vivo, we showed HFOs in the DG at just 1 month of age. 14 Our study is the first to show that the DG dominates the activity that occurs during IIS.…”

Section: The Dg As a Possible Source Of Iis In Ad Modelsmentioning

confidence: 79%

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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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

Cited by 23 publications

References 161 publications

Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer's disease mouse model

Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer's disease mouse model

High‐frequency oscillations (250–500 Hz) in animal models of Alzheimer's disease and two animal models of epilepsy

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

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