Intracellular calcium homeostasis and its dysregulation underlying epileptic seizures

Zhou, Xu; Chen, Zengqiang; Lin, Xiao; Zhong, Yanting; Liu, Yang; Wu, Jianhao; Ting, Hua

doi:10.1016/j.seizure.2022.11.007

Cited by 11 publications

(3 citation statements)

References 176 publications

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“…The regulatory effect of calcium homeostasis on ictal activity is even more complex because it interacts not only with neuronal activity but also with nonneuronal cells (astrocytes and glia) [86]. Several molecular components are responsible for maintaining intracellular calcium homeostasis; these include voltage-dependent calcium channels, ER-resident IP3 receptors, ryanodine receptors, and calcium-binding proteins and are involved in the calcium dysregulation underlying epileptic seizures [87,88]. In an animal model of TLE induced by kainic acid in mice, Cav3.1 T-type calcium channels were shown to play a modulatory role in the duration and frequency of hippocampal seizures, as well as epileptogenicity, mostly during acute periods [89].…”

Section: Discussionmentioning

confidence: 99%

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

Diaz-Villegas,

Pichardo-Macías,

Juárez-Méndez

et al. 2024

IJMS

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Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT–qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT–qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients.

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Section: Discussionmentioning

confidence: 99%

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

Diaz-Villegas,

Pichardo-Macías,

Juárez-Méndez

et al. 2024

IJMS

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“…The known mechanisms for the occurrence of epilepsy due to calcium ions dysregulation include glutamate receptor (GluR) overexcitation and changes in voltage-gated calcium channels (VGCC) activity ( Wojda et al, 2008 ). In addition, several molecular components accountable for the maintenance of the intracellular calcium ion homeostasis, including VGCCs, endoplasmic reticulum calcium sensor stromal interaction molecule (STIM), the plasma membrane calcium channel Orai, IP3Rs and RyRs, SERCA, and transmembrane and coiled-coil domains 1 (TMCO1), have been revealed to be involved in calcium ion dysregulation that underlies epileptic seizures ( Zhou et al, 2022 ). We speculate that insufficient calcium ions influx in the cells might have activated negative compensatory mechanisms leading to GluR over excitation as well as dysregulated intracellular calcium ions homeostasis leading to epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

Kessi

Chen

Pan

et al. 2023

Front. Mol. Neurosci.

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ObjectiveTo investigate the pathogenesis of three novel de novo CACNA1C variants (p.E411D, p.V622G, and p.A272V) in causing neurodevelopmental disorders and arrhythmia.MethodsSeveral molecular experiments were carried out on transfected human embryonic kidney 293 (HEK 293) and Chinese hamster ovary (CHO) cells to explore the effects of p.E411D, p.V622G, and p.A272V variants on electrophysiology, mitochondrial and lysosomal functions. Electrophysiological studies, RT-qPCR, western blot, apoptosis assay, mito-tracker fluorescence intensity, lyso-tracker fluorescence intensity, mitochondrial calcium concentration test, and cell viability assay were performed. Besides, reactive oxygen species (ROS) levels, ATP levels, mitochondrial copy numbers, mitochondrial complex I, II, and cytochrome c functions were measured.ResultsThe p.E411D variant was found in a patient with attention deficit-hyperactive disorder (ADHD), and moderate intellectual disability (ID). This mutant demonstrated reduced calcium current density, mRNA, and protein expression, and it was localized in the nucleus, cytoplasm, lysosome, and mitochondria. It exhibited an accelerated apoptosis rate, impaired autophagy, and mitophagy. It also demonstrated compromised mitochondrial cytochrome c oxidase, complex I, and II enzymes, abnormal mitochondrial copy numbers, low ATP levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, and elevated mitochondrial calcium ions. The p.V622G variant was identified in a patient who presented with West syndrome and moderate global developmental delay. The p.A272V variant was found in a patient who presented with epilepsy and mild ID. Both mutants (p.V622G and p.A272V) exhibited reduced calcium current densities, decreased mRNA and protein expressions, and they were localized in the nucleus, cytoplasm, lysosome, and mitochondria. They exhibited accelerated apoptosis and proliferation rates, impaired autophagy, and mitophagy. They also exhibited abnormal mitochondrial cytochrome c oxidase, complex I and II enzymes, abnormal mitochondrial copy numbers, low ATP, high ROS levels, abnormal mitochondria fluorescence intensity, impaired mitochondrial fusion and fission, as well as elevated mitochondrial calcium ions.ConclusionThe p.E411D, p.V622G and p.A272V mutations of human CACNA1C reduce the expression level of CACNA1C proteins, and impair mitochondrial and lysosomal functions. These effects induced by CACNA1C variants may contribute to the pathogenesis of CACNA1C-related disorders.

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“…We linked the activation of HMM states with dynamic temporal characteristics in TLE to gene expression levels. TLE is a complex disorder in uenced by elements such as synaptic connectivity, receptor functions, and ion channel abnormalities, which have been shown to predispose individuals to TLE [53].…”

Section: Link Between Neural Con Guration and Gene Expressionmentioning

confidence: 99%

Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

Qin,

Zhou,

Sun

et al. 2024

Preprint

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Backgroud Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the dynamic changes in brain activity at each time point remain unclear, as does the potential molecular mechanisms associated with the dynamic temporal characteristics of TLE. Methods Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data was then used to conduct HMM analysis on rs-fMRI data from TLE patients and an HC group in order to explore the intricate temporal dynamics of brain activity in TLE patients with cognitive impairment (TLE-CI). Additionally, we aim to examine the gene expression profiles associated with the dynamic modular characteristics in TLE patients using the Allen Human Brain Atlas (AHBA) database. Results Five HMM states were identified in this study. Compared with HCs, TLE and TLE-CI patients exhibited distinct changes in dynamics, including fractional occupancy, lifetimes, mean dwell time and switch rate. Furthermore, transition probability across HMM states were significantly different between TLE and TLE-CI patients (p < 0.05). The temporal reconfiguration of states in TLE and TLE-CI patients was associated with several brain networks (including the high-order default mode network (DMN), subcortical network (SCN), and cerebellum network (CN). Furthermore, a total of 1580 genes were revealed to be significantly associated with dynamic brain states of TLE, mainly enriched in neuronal signaling and synaptic function. Conclusions This study provides new insights into characterizing dynamic neural activity in TLE. The brain network dynamics defined by HMM analysis may deepen our understanding of the neurobiological underpinnings of TLE and TLE-CI, indicating a linkage between neural configuration and gene expression in TLE.

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Intracellular calcium homeostasis and its dysregulation underlying epileptic seizures

Cited by 11 publications

References 176 publications

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

Changes in the Dentate Gyrus Gene Expression Profile Induced by Levetiracetam Treatment in Rats with Mesial Temporal Lobe Epilepsy

Disruption of mitochondrial and lysosomal functions by human CACNA1C variants expressed in HEK 293 and CHO cells

Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

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