Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease

Lam, Alice; Deck, Gina; Goldman, Alica M.; Eskandar, Emad N.; Noebels, Jeffrey L.; Cole, Andrew J.

doi:10.1038/nm.4330

Cited by 311 publications

(299 citation statements)

References 27 publications

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“…Altered PV IN inhibition on pyramidal cells is closely linked to abnormal network oscillations and cognitive functions. Network hyperexcitability and epileptiform events have been observed in most mouse models of AD (Palop et al, 2007, 2011; Busche et al, 2008; Palop and Mucke, 2009; Harris et al, 2010; Roberson et al, 2011; Yan et al, 2012; Busche and Konnerth, 2016) and in AD patients using high resolution recordings (Lam et al, 2017). Hypersynchronous network activities have been shown to emerge during reduced gamma oscillation, which is a rhythm that depends on the activities of fast-spiking PV INs and contributes to cognitive functions (Cardin et al, 2009; Sohal et al, 2009; Buzsáki and Wang, 2012; Sohal, 2012; Cho et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it remains difficult to study potential epileptiform activities in patients with conventional EEG electrodes because the abberant activity takes place in deep temporal structures. A recent study using foramen ovale electrodes positioned adjacent to the mesial temporal lobe revealed clinically silent hippocampal seizures and epileptiform spikes during sleep, a period especially important for memory consolidation (Lam et al, 2017). In urethane-anesthetized App NL-F mice, abnormal gamma oscillations were observed in the entorhinal cortex, including reduced theta-γ coupling and impaired phase-locking of layer 2/3 pyramidal cell spiking activities (Nakazono et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, neuronal hyperactivity, network hyperexcitability, and spontaneous epileptiform activity have been observed in human amyloid precursor protein (hAPP) transgenic mouse models with high levels of Aβ (Palop et al, 2007, 2011; Busche et al, 2008; Palop and Mucke, 2009; Harris et al, 2010; Roberson et al, 2011; Yan et al, 2012; Busche and Konnerth, 2016). Hypersynchronous network activity, also observed in AD patients (Lam et al, 2017), may further contribute to the emergence of AD symptoms such as cognitive impairment in early stages of the disease (Noebels, 2011; Bakker et al, 2012; Scharfman, 2012). Specifically, electrophysiological studies in hAPPJ20 mice have revealed decreased intrinsic excitability of GABAergic parvalbumin-expressing interneurons (PV INs), which then led to aberrant network activity and cognitive deficits in the animals (Verret et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Chen

Saito

Saido

et al. 2018

eNeuro

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Alzheimer’s disease (AD) is a neurodegenerative disorder that has become a compelling global public health concern. Besides pathological hallmarks such as extracellular amyloid plaques, intracellular neurofibrillary tangles (NFTs), and loss of neurons and synapses, clinical reports have shown that epileptiform activity, even seizures, can occur early in the disease. Aberrant synaptic and network activities as well as epileptiform discharges have also been observed in various mouse models of AD. The new AppNL-F mouse model is generated by a gene knock-in approach and there are limited studies on basic synaptic properties in AppNL-F mice. Therefore, we applied quantitative methods to analyze spontaneous excitatory and inhibitory synaptic events in parietal cortex layer 2/3 pyramidal cells. First, by an objective amplitude distribution analysis, we found decreased amplitudes of spontaneous IPSCs (sIPSCs) in aged AppNL-F mice caused by a reduction in the amplitudes of the large sIPSCs with fast rates of rise, consistent with deficits in the function of parvalbumin-expressing interneurons (PV INs). Second, we calculated the burstiness and memory in a series of successive synaptic events. Lastly, by using a novel approach to determine the excitation-to-inhibition (E/I) ratio, we found no changes in the AppNL-F mice, indicating that homeostatic mechanisms may have maintained the overall balance of excitation and inhibition in spite of a mildly impaired PV IN function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Chen

Saito

Saido

et al. 2018

eNeuro

View full text Add to dashboard Cite

show abstract

“…In addition to increased incidence of seizures in AD patients (Vossel et al, 2017), a recent study revealed subclinical hippocampal seizures and spikes during sleep in AD patients (Lam et al, 2017). Studies of AD mouse models with cerebral Aβ and/or tau pathologies have demonstrated increased incidence of spontaneous or induced seizures, EEG evidence of global seizure-like activity, and increased excitability of hippocampal and entorhinal cortex projection neurons measured using intracellular electrodes (García-Cabrero et al, 2013; Kam et al, 2016; Kazim et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Liu

Stein

et al. 2018

Neurobiology of Aging

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Alzheimer’s disease (AD) is characterized by progressive cognitive impairment and by extensive neuronal loss associated with extracellular amyloid β-peptide (Aβ) plaques and intraneuronal tau pathology in temporal and parietal lobes. AD patients are at increased risk for epileptic seizures, and data from experimental models of AD suggest that aberrant neuronal network activity occurs early in the disease process before cognitive deficits and neuronal degeneration. The contributions of Aβ and/or tau pathologies to dysregulation of neuronal network activity are unclear. Using a transgenic mouse model of AD (3 × TgAD mice) in which there occurs differential age-dependent development of tau and Aβ plaque pathologies, we applied analysis of resting state functional magnetic resonance imaging regional homogeneity, a measure of local synchronous activity, to discriminate the effects of Aβ and tau on neuronal network activity throughout the brain. Compared to age-matched wild-type mice, 6- to 8-month-old 3 × TgAD mice exhibited increased regional homogeneity in the hippocampus and parietal and temporal cortices, regions with tau pathology but not Aβ pathology at this age. By 18–24 months of age, 3 × TgAD mice exhibited extensive tau and Aβ pathologies involving the hippocampus and multiple functionally related brain regions, with a spatial expansion of increased local synchronous activity to include those regions. Our findings demonstrate that age-related brain regional hypersynchronous activity is associated with early tau pathology in a mouse model, consistent with a role for early tau pathology in the neuronal circuit hyperexcitability that is believed to precede and contribute to neuronal degeneration in AD.

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“…In particular, age explains over 15% individual-level variation in module 4 (cortex), module 7 (hippocampus), and module 8 (all brain tissues). Notably, the hippocampus is associated with memory, in particular long-term memory, and is vulnerable to Alzheimer's disease (Lam et al 2017). In the module 4, GPR26 is found to be the top age-related gene.…”

Section: Fine Structures In Subtensors Of Similar Tissuesmentioning

confidence: 99%

Three-way clustering of multi-tissue multi-individual gene expression data using constrained tensor decomposition

Wang

Fischer

Song

2017

Preprint

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The advent of next generation sequencing methods has led to an increasing availability of large, multi-tissue datasets which contain gene expression measurements across different tissues and individuals. In this setting, variation in expression levels arises due to contributions specific to genes, tissues, individuals, and interactions thereof. Classical clustering methods are illsuited to explore these three-way interactions, and struggle to fully extract the insights into transcriptome complexity and regulation contained in the data. Thus, to exploit the multimode structure of the data, new methods are required. To this end, we propose a new method, called MultiCluster, based on constrained tensor decomposition which permits the investigation of transcriptome variation across individuals and tissues simultaneously. Through simulation and application to the GTEx RNA-seq data, we show that our tensor decomposition identifies three-way clusters with higher accuracy, while being 11x faster, than the competing Bayesian method. For several age-, race-, or gender-related genes, the tensor projection approach achieves increased significance over single-tissue analysis by two orders of magnitude. Our analysis finds gene modules consistent with existing knowledge while further detecting novel candidate genes exhibiting either tissue-, individual-, or tissue-by-individual specificity. These identified genes and gene modules offer bases for future study, and the uncovered multi-way specificities provide a finer, more nuanced snapshot of transcriptome variation than previously possible.

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Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease

Cited by 311 publications

References 27 publications

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

Brain regional synchronous activity predicts tauopathy in 3×TgAD mice

Three-way clustering of multi-tissue multi-individual gene expression data using constrained tensor decomposition

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