Persistent Synchronized Bursting Activity in Cortical Tissues With Low Magnesium Concentration: A Modeling Study

2006 ◽  
Vol 95 (2) ◽  
pp. 1049-1067 ◽  
Author(s):  
David Golomb ◽  
Anat Shedmi ◽  
Rodica Curtu ◽  
G. Bard Ermentrout
Keyword(s):  
Decay Time ◽  
Epileptiform Activity ◽  
Magnesium Concentration ◽  
Quiescent State ◽  
Network Behavior ◽  
Low Magnesium ◽  
A Cell ◽  
Layer V ◽  
Physiological Values ◽  
Bursting Activity

We explore the mechanism of synchronized bursting activity with frequency of ∼10 Hz that appears in cortical tissues at low extracellular magnesium concentration [Mg2+]o. We hypothesize that this activity is persistent, namely coexists with the quiescent state and depends on slow N-methyl-d-aspartate (NMDA) conductances. To explore this hypothesis, we construct and investigate a conductance-based model of excitatory cortical networks. Population bursting activity can persist for physiological values of the NMDA decay time constant (∼100 ms). Neurons are synchronized at the time scale of bursts but not of single spikes. A reduced model of a cell coupled to itself can encompass most of this highly synchronized network behavior and is analyzed using the fast-slow method. Synchronized bursts appear for intermediate values of the NMDA conductance gNMDA if NMDA conductances are not too fast. Regular spiking activity appears for larger gNMDA. If the single cell is a conditional burster, persistent synchronized bursts become more robust. Weakly synchronized states appear for zero AMPA conductance gAMPA. Enhancing gAMPA increases both synchrony and the number of spikes within bursts and decreases the bursting frequency. Too strong gAMPA, however, prevents the activity because it enhances neuronal intrinsic adaptation. When [Mg2+]o is increased, higher gNMDA values are needed to maintain bursting activity. Bursting frequency decreases with [Mg2+]o, and the network is silent with physiological [Mg2+]o. Inhibition weakly decreases the bursting frequency if inhibitory cells receive enough NMDA-mediated excitation. This study explains the importance of conditional bursters in layer V in supporting epileptiform activity at low [Mg2+]o.

A ribosomal defect in dystrophic hamsters

1983 ◽  
Vol 61 (1) ◽  
pp. 1-7 ◽  
Author(s):  
C. Jolicoeur ◽  
L. Brakier-Gingras
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Wheat Germ ◽  
Magnesium Concentration ◽  
Wheat Germ Extract ◽  
Soluble Factors ◽  
Low Magnesium ◽  
Age Dependent ◽  
A Cell ◽  
Synthesis Activity

Polysomes were isolated from the skeletal muscle, the heart, and the liver of dystrophic and normal hamsters and their protein synthesis activity was assessed in a cell-free wheat germ extract as a source of soluble factors and tRNAs. Our results show that there is a shift of the optimal magnesium concentration required for protein synthesis with polysomes from the skeletal muscle and the heart of dystrophic hamsters, as compared with control hamsters. As a consequence of this shift, polysomes from the skeletal muscle and the heart of dystrophic hamsters were less active than normal ones at low magnesium concentrations, but more active at high magnesium concentrations. These changes in activity were age dependent since, with skeletal muscle, they were observed at 30 days and disappeared at 60 days but reappeared at 120 and 200 days. With heart polysomes, on the other hand, the changes in activity were observed at 60 days but not in younger or older animals. No change in activity was observed with liver polysomes. Similar results were obtained when endogenous mRNAs were replaced by an exogenous messenger such as poly(U). This suggests that the differences in protein synthesis activity between polysomes from dystrophic and normal hamsters are not due to changes in the endogenous mRNAs but result from a ribosomal abnormality.

Cellular Differentiation in Response to Nutrient Availability: The Repressor of Meiosis, Rme1p, Positively Regulates Invasive Growth in Saccharomyces cerevisiae

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1045-1058
Author(s):  
Dewald van Dyk ◽  
Guy Hansson ◽  
Isak S Pretorius ◽  
Florian F Bauer
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cellular Differentiation ◽  
Promoter Sequence ◽  
Quiescent State ◽  
Invasive Growth ◽  
Limited Growth ◽  
Yeast Saccharomyces Cerevisiae ◽  
A Cell ◽  
Signaling Modules ◽  
Differentiation Pathways

Abstract In the yeast Saccharomyces cerevisiae, the transition from a nutrient-rich to a nutrient-limited growth medium typically leads to the implementation of a cellular adaptation program that results in invasive growth and/or the formation of pseudohyphae. Complete depletion of essential nutrients, on the other hand, leads either to entry into a nonbudding, metabolically quiescent state referred to as G0 in haploid strains or to meiosis and sporulation in diploids. Entry into meiosis is repressed by the transcriptional regulator Rme1p, a zinc-finger-containing DNA-binding protein. In this article, we show that Rme1p positively regulates invasive growth and starch metabolism in both haploid and diploid strains by directly modifying the transcription of the FLO11 (also known as MUC1) and STA2 genes, which encode a cell wall-associated protein essential for invasive growth and a starch-degrading glucoamylase, respectively. Genetic evidence suggests that Rme1p functions independently of identified signaling modules that regulate invasive growth and of other transcription factors that regulate FLO11 and that the activation of FLO11 is dependent on the presence of a promoter sequence that shows significant homology to identified Rme1p response elements (RREs). The data suggest that Rme1p functions as a central switch between different cellular differentiation pathways.

scholarly journals Maternal immune activation induces methylation changes in schizophrenia genes

2022 ◽  
Author(s):  
Tom Johnson ◽  
Defne Saatci ◽  
Lahiru Handunnetthi
Keyword(s):  
Environmental Risk ◽  
Immune Activation ◽  
Pyramidal Neurons ◽  
Fold Change ◽  
Adult Brain ◽  
Maternal Immune Activation ◽  
Differentially Methylated Genes ◽  
A Cell ◽  
Layer V ◽  
Upregulated Genes

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Infection driven maternal immune activation (MIA) during pregnancy is a key environmental risk factor. However, little is known about how MIA during pregnancy could contribute to adult-onset schizophrenia. In this study, we investigated if maternal immune activation induces changes in methylation of genes linked to schizophrenia. We found that differentially expressed genes in schizophrenia brain were significantly enriched among MIA induced differentially methylated genes in the foetal brain in a cell-type-specific manner. Upregulated genes in layer V pyramidal neurons were enriched among hypomethylated genes at gestational day 9 (fold change = 1.57 , FDR = 0.049) and gestational day 17 (fold change = 1.97 , FDR = 0.0006). We also found that downregulated genes in GABAergic Rosehip interneurons were enriched among hypermethylated genes at gestational day 17 (fold change = 1.62, FDR= 0.03). Collectively, our results highlight a connection between MIA driven methylation changes during gestation and schizophrenia gene expression signatures in the adult brain. These findings carry important implications for early preventative strategies in schizophrenia.

The Effect of Low Magnesium Concentration on Ictal Discharges In A Non-Synaptic Model

2020 ◽  
pp. 2050070
Author(s):  
Antônio Márcio Rodrigues ◽  
Delmo Benedito Silva ◽  
Maísa Ferreira Miranda ◽  
Silvia Cristina Braga da Silva ◽  
Luiz Eduardo Canton Santos ◽  
...  
Keyword(s):  
Computer Simulations ◽  
Prolonged Exposure ◽  
Joint Effect ◽  
Magnesium Concentration ◽  
Neuronal Cultures ◽  
Electrochemical Characteristics ◽  
Cellular Functions ◽  
Physiological Concentration ◽  
Low Magnesium ◽  
Epileptiform Discharges

Magnesium (Mg[Formula: see text] is an essential mineral for several cellular functions. The concentration of this ion below the physiological concentration induces recurrent neuronal discharges both in slices of the hippocampus and in neuronal cultures. These epileptiform discharges are initially sensitive to the application of [Formula: see text]-methyl-D-aspartate (NMDA) receptor antagonists, but these antagonists may lose their effectiveness with prolonged exposure to low [Mg[Formula: see text]], when extracellular Ca[Formula: see text] reduction occurs, typical of ictal periods, indicating the absence of synaptic connections. The study herein presented aimed at investigating the effect of reducing the [Mg[Formula: see text]] during the induction of Nonsynaptic Epileptiform Activities (NSEA). As an experimental protocol, NSEA were induced in rat hippocampal dentate gyrus (DG), using a bath solution containing high-K[Formula: see text] and zero-added-Ca[Formula: see text]. Additionally, computer simulations were performed using a mathematical model that represents electrochemical characteristics of the tissue of the DG granular layer. The experimental results show that the reduction of [Mg[Formula: see text]] causes an increase in the duration of the ictal period and a reduction in the interictal period, intensifying epileptiform discharges. The computer simulations suggest that the reduction of the Mg[Formula: see text] level intensifies the epileptiform discharges by a joint effect of reducing the surface charge screening and reducing the activity of the Na/K pump.

Magnesium Regulates the Circadian Oscillator in Cyanobacteria

2019 ◽  
Vol 34 (4) ◽  
pp. 380-390 ◽  
Author(s):  
Young M. Jeong ◽  
Cristiano Dias ◽  
Casey Diekman ◽  
Helene Brochon ◽  
Pyonghwa Kim ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Circadian Clock ◽  
Biological Rhythms ◽  
Circadian Oscillator ◽  
Magnesium Concentration ◽  
Circadian Oscillation ◽  
Magnesium Homeostasis ◽  
Low Magnesium

The circadian clock controls 24-h biological rhythms in our body, influencing many time-related activities such as sleep and wake. The simplest circadian clock is found in cyanobacteria, with the proteins KaiA, KaiB, and KaiC generating a self-sustained circadian oscillation of KaiC phosphorylation and dephosphorylation. KaiA activates KaiC phosphorylation by binding the A-loop of KaiC, while KaiB attenuates the phosphorylation by sequestering KaiA from the A-loop. Structural analysis revealed that magnesium regulates the phosphorylation and dephosphorylation of KaiC by dissociating from and associating with catalytic Glu residues that activate phosphorylation and dephosphorylation, respectively. High magnesium causes KaiC to dephosphorylate, whereas low magnesium causes KaiC to phosphorylate. KaiC alone behaves as an hourglass timekeeper when the magnesium concentration is alternated between low and high levels in vitro. We suggest that a magnesium-based hourglass timekeeping system may have been used by ancient cyanobacteria before magnesium homeostasis was established.

Zinc and glycine do not modify low-magnesium-induced epileptiform activity in the immature neocortex in vitro

1989 ◽  
Vol 3 (2) ◽  
pp. 174-177 ◽  
Author(s):  
Elisabeth Hegstad ◽  
Iver A Langmoen ◽  
John J Hablitz
Keyword(s):  
Epileptiform Activity ◽  
Low Magnesium

Influence of manufacturing conditions on the bioavailability of magnesium in calcined magnesites measured in vivo and in vitro

1996 ◽  
Vol 127 (3) ◽  
pp. 377-385 ◽  
Author(s):  
C. L. Adam ◽  
R. G. Hemingway ◽  
N. S. Ritchie
Keyword(s):  
Urinary Output ◽  
Magnesium Concentration ◽  
Particle Sizes ◽  
Calcination Temperatures ◽  
Low Magnesium ◽  
Veterinary School ◽  
Grade Material ◽  
Plasma Magnesium

SUMMARYDietary calcined magnesite supplements of different particle sizes and temperatures of calcination were examined at Glasgow University Veterinary School in 1981. Balance experiments with wether sheep revealed that particle sizes < 75, 75–150, 150–250 and 500–1000 μm diameter of a feed-grade calcined magnesite all increased urinary output of magnesium to a similar extent but the apparent magnesium availability coefficient for the 500–1000 μm diameter fraction (0·03) was significantly less than for fractions of smaller diameter (0·17–0·23) (P < 0·01). A 1000–2000 μm fraction of fertilizer-grade material had an apparent availability of 0·18 but had the least effect on urinary magnesium output. Calcination temperatures of 800, 900 and 1100 °C significantly increased apparent availability (c. 0·46)compared with that for temperatures of 500 and 650 °C (c. 0·12) (P < 0·01), and significantly increased urinary output of magnesium. Losses of magnesium from these supplements incubated in the rumen of cows at grass in 24 μm mesh nylon bags showed some correlations with their apparent availability and urinary magnesium output. Solubility in molar ammonium nitrate showed some good correlations with urinary magnesium output but not with magnesium availability. Supplementation of a low magnesium diet given to lactating ewes with fine particle (< 75μm) calcined magnesite resulted in significantly greater increases in plasma magnesium concentration than when coarse particle material (500–1000 μm) was given (P < 0·05), but magnesites calcined at 650 and 800 °C induced similar changes in plasma magnesium.

scholarly journals Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

2021 ◽  
Author(s):  
Nidheesh Thadathil ◽  
Evan Nicklas ◽  
Sabira Jazir ◽  
Tommy L Lewis ◽  
Arlan Richardson ◽  
...  
Keyword(s):  
Term Treatment ◽  
Short Term Treatment ◽  
Cell Death Pathway ◽  
Age Related ◽  
A Cell ◽  
The Central Nervous System ◽  
Layer V ◽  
Molecular Patterns ◽  
Old Mice ◽  
The Brain

Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induce inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which causes membrane binding and permeabilization were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers (Iba-1 and GFAP) of neuroinflammation in the brains of old mice and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

scholarly journals A Feedforward Mechanism for Epileptogenesis Regulated by Lactate Dehydrogenase A

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Marcelle Altshuler ◽  
Alexander Ksendzovsky ◽  
Muznbanu Bachani ◽  
Stuart Walbridge ◽  
Sara Inati ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Microelectrode Array ◽  
Cortical Cell ◽  
Metabolic Phenotype ◽  
Neuronal Membrane ◽  
Burst Frequency ◽  
Low Magnesium ◽  
Resected Tissue ◽  
Novel Concept ◽  
Bursting Activity

Abstract INTRODUCTION Despite the ketogenic diet's successful use since the 1920s, epilepsy as a disease of energy metabolism is a novel concept. We previously established that seizures deplete neuronal energy stores and reprogram neurons from aerobic to glycolytic metabolic phenotype, marked by upregulation of lactate dehydrogenase A (LDHA). LDHA has recently been shown to play a role in neuronal membrane depolarization and epileptogenesis. We show here that LDHA upregulation through HIF1a may lead to seizure formation. METHODS Resected tissue from 11 epileptic patients were probed for LDHA expression. To study the electrophysiological consequences of LDHA, we used a mixed rat cortical cell culture model on a microelectrode array (MEA). Furthermore, we developed a novel murine model of chronic focal cortical epilepsy to establish HIF1a's role in mediating LDHA expression and seizure formation. Finally, we used a lentivirus vector to directly upregulate LDHA in neurons cultured on an MEA to measure neuronal bursting. RESULTS We found LDHA increased significantly in epileptic tissue versus nonepileptic tissue. Induction of seizure activity in cultured neurons with low magnesium resulted in increased LDHA and subsequently increased baseline bursting over 10 d. Inhibition of LDHA activity with stiripentol and isosafrole decreased the overall burst frequency. Cells that were induced to upregulate LDHA via DMOG, an upstream HIF1a potentiator, showed a significant increase in baseline bursting activity. Furthermore, placement of cobalt, a HIF1a stabilizer, into the frontal cortex of mice caused chronic seizures emanating from perilesion cortex which showed increased LDHA. Finally, direct LDHA upregulation resulted in increased bursting activity confirming that LDHA may lead to seizure formation. CONCLUSION Overall, our data show that LDHA, regulated by HIF1a, can contribute to seizure development. These data suggest a novel molecular mechanism for the pathogenesis of epilepsy where seizures cause LDHA upregulation which then further drives seizures, leading to a cycle of epileptogenesis.

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