scholarly journals Ion dynamics at the energy-deprived tripartite synapse

2021 ◽  
Vol 17 (6) ◽  
pp. e1009019
Author(s):  
Manu Kalia ◽  
Hil G. E. Meijer ◽  
Stephan A. van Gils ◽  
Michel J. A. M. van Putten ◽  
Christine R. Rose
Keyword(s):  
Extracellular Space ◽  
Membrane Potentials ◽  
Cellular Damage ◽  
Biophysical Model ◽  
Energy Conditions ◽  
Cell Swelling ◽  
Pathological State ◽  
Ischemic Damage ◽  
Ion Gradients ◽  
Energy Deprivation

The anatomical and functional organization of neurons and astrocytes at ‘tripartite synapses’ is essential for reliable neurotransmission, which critically depends on ATP. In low energy conditions, synaptic transmission fails, accompanied by a breakdown of ion gradients, changes in membrane potentials and cell swelling. The resulting cellular damage and cell death are causal to the often devastating consequences of an ischemic stroke. The severity of ischemic damage depends on the age and the brain region in which a stroke occurs, but the reasons for this differential vulnerability are far from understood. In the present study, we address this question by developing a comprehensive biophysical model of a glutamatergic synapse to identify key determinants of synaptic failure during energy deprivation. Our model is based on fundamental biophysical principles, includes dynamics of the most relevant ions, i.e., Na+, K+, Ca2+, Cl− and glutamate, and is calibrated with experimental data. It confirms the critical role of the Na+/K+-ATPase in maintaining ion gradients, membrane potentials and cell volumes. Our simulations demonstrate that the system exhibits two stable states, one physiological and one pathological. During energy deprivation, the physiological state may disappear, forcing a transit to the pathological state, which can be reverted when blocking voltage-gated Na+ and K+ channels. Our model predicts that the transition to the pathological state is favoured if the extracellular space fraction is small. A reduction in the extracellular space volume fraction, as, e.g. observed with ageing, will thus promote the brain’s susceptibility to ischemic damage. Our work provides new insights into the brain’s ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes.

scholarly journals Ion dynamics at the energy-deprived tripartite synapse

2021 ◽  
Author(s):  
Manu Kalia ◽  
Hil G.E. Meijer ◽  
Stephan A. van Gils ◽  
Michel J.A.M. van Putten ◽  
Christine R. Rose
Keyword(s):  
Experimental Data ◽  
Extracellular Space ◽  
Membrane Potentials ◽  
Energy Conditions ◽  
Cell Swelling ◽  
Pathological State ◽  
Ischemic Damage ◽  
Ion Gradients ◽  
Energy Deprivation ◽  
The Brain

AbstractThe anatomical and functional organization of neurons and astrocytes at ‘tripartite synapses’ is essential for reliable neurotransmission, which critically depends on ATP. In low energy conditions, synaptic transmission fails, accompanied by a breakdown of ion gradients, changes in membrane potentials and cell swelling. The resulting cellular damage and cell death are causal to the often devastating consequences of an ischemic stroke. The severity of ischemic damage depends on the age and the brain region in which a stroke occurs, but the reasons for this differential vulnerability are far from understood. In the present study, we address this question by developing a comprehensive biophysical model of a glutamatergic synapse to identify key determinants of synaptic failure during energy deprivation. Our model is based on fundamental biophysical principles, includes dynamics of the most relevant ions, i.e., Na+, K+, Ca2+, Cl− and glutamate, and is calibrated with experimental data. It confirms the critical role of the Na+/K+-ATPase in maintaining ion gradients, membrane potentials and cell volumes. Our simulations demonstrate that the system exhibits two stable states, one physiological and one pathological. During energy deprivation, the physiological state may disappear, forcing a transit to the pathological state, which can be reverted when blocking voltage-gated Na+ and K+ channels. Our model predicts that the transition to the pathological state is favoured if the extracellular space fraction is small. A reduction in the extracellular space volume fraction, as, e.g. observed with ageing, will thus promote the brain’s susceptibility to ischemic damage. Our work provides new insights into the brain’s ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes.Author summaryThe brain consumes energy to keep ion concentrations at normal working conditions. In the case of energy deprivation (ED), e.g., during a stroke, synaptic communication fails first. Inspired by our recent experimental work on ED, we formulated a novel computational model to explore initial events during ED. Our model reproduces time courses for several ions from different experimental data. In some cases, the system returns to baseline upon restoring energy supply. In others, we observe that neurons and astrocytes cannot recover accompanied by cell swelling. There is a threshold depending on the depth and duration of ATP depletion differentiating these cases. Also, smaller extracellular spaces hamper recovery more. This result may explain clinical observations of increased vulnerability to stroke as the size of the extracellular space shrinks with ageing.

scholarly journals Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 18
Author(s):  
Amelia Charlton ◽  
Jessica Garzarella ◽  
Karin A. M. Jandeleit-Dahm ◽  
Jay C. Jha
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Tissue Injury ◽  
Cardiovascular Complications ◽  
Therapeutic Strategies ◽  
Cellular Damage ◽  
Antioxidant Defenses ◽  
Pathological State ◽  
Oxygen Species ◽  
Emerging Therapies

Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes.

scholarly journals Water Compartmentalization and Spread of Ischemic Injury in Thick-Slice Ischemia Model

2002 ◽  
Vol 22 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Sabina Hrabětová ◽  
Kevin C. Chen ◽  
Daniel Masri ◽  
Charles Nicholson
Keyword(s):  
Water Content ◽  
Extracellular Space ◽  
Cell Swelling ◽  
Extracellular Potassium ◽  
Tissue Water ◽  
Diffusion Analysis ◽  
Artificial Cerebrospinal Fluid ◽  
Water Redistribution ◽  
Total Tissue

Water compartmentalization was studied in a thick-slice (1000 μm) model of ischemia by combining water-content measurements with extracellular diffusion analysis. Thick slices bathed in artificial cerebrospinal fluid continually gained water. Total tissue water content was increased by 67% after 6 hours of the incubation. Diffusion measurements using the tetramethylammonium method showed that the extracellular space, typically occupying 20% of brain tissue in vivo, was decreased to 10% at 30 minutes and 15% at 6 hours in both deep and superficial layers of thick slices. Quantification of water compartmentalization revealed that water moved initially from the extracellular space into the cells. Later, however, both compartments gained water. The initial cell swelling was accompanied by dramatic shifts in potassium. An initial rise of extracellular potassium to about 50 mmol/L was measured with a potassium-selective microelectrode positioned in the center of the thick slice; the concentration decreased slowly afterwards. Potassium content analysis revealed a 63% loss of tissue potassium within two hours of the incubation. In thick slices, ionic shifts, water redistribution, and a loss of synaptic transmission occur in both deep and superficial layers, indicating the spread of ischemic conditions even to areas with an unrestricted supply of nutrients.

GABA Transporter Preserving Ongoing Spontaneous Neuronal Activity at Firing Subthreshold

2009 ◽  
Vol 21 (6) ◽  
pp. 1683-1713 ◽  
Author(s):  
Osamu Hoshino
Keyword(s):  
Neuronal Activity ◽  
Extracellular Space ◽  
Transport Mechanism ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Gaba Transporter ◽  
Cell Assemblies ◽  
Time Period ◽  
Ambient Gaba ◽  
Spontaneous Neuronal Activity

There has been compelling evidence that the GABA transporter is crucial not only for removing gamma-aminobutyric acid (GABA) from but also releasing it into extracellular space, thereby clamping ambient GABA (GABA in extracellular space) at a certain level. The ambient GABA is known to activate extrasynaptic GABA receptors and provide tonic inhibitory current into neurons. We investigated how the transporter regulates the level of ambient GABA, mediates tonic neuronal inhibition, and influences ongoing spontaneous neuronal activity. A cortical neural network model is proposed in which GABA transporters on lateral (L) and feedback (F) inhibitory (GABAergic) interneurons are functionally made. Principal (P) cell assemblies participate in expressing information about elemental sensory features. At membrane potentials below the reversal potential, there is net influx of GABA, whereas at membrane potentials above the reversal potential, there is net efflux of GABA. Through this transport mechanism, ambient GABA concentration is kept within a submicromolar range during an ongoing spontaneous neuronal activity time period. Here we show that the GABA transporter on L cells regulates the overall level of ambient GABA across cell assemblies, and that on F cells it does so within individual cell assemblies. This combinatorial regulation of ambient GABA allows P cells to oscillate near firing threshold during the ongoing time period, thereby reducing their reaction time to externally applied stimuli. We suggest that the GABA transporter, with its forward and reverse transport mechanism, could regulate the ambient GABA. This transporter-mediated ambient GABA regulation may contribute to establishing an ongoing subthreshold neuronal state by which the network can respond rapidly to subsequent sensory input.

scholarly journals DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview

2021 ◽  
Vol 22 (5) ◽  
pp. 2439
Author(s):  
Baptiste Balança ◽  
Laurent Desmurs ◽  
Jérémy Grelier ◽  
Armand Perret-Liaudet ◽  
Anne-Claire Lukaszewicz
Keyword(s):  
Brain Injury ◽  
Acute Phase ◽  
Extracellular Space ◽  
Acute Brain Injury ◽  
Cellular Damage ◽  
Mechanical Trauma ◽  
Growth And Survival ◽  
Cell Clearance ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives

scholarly journals Extracellular space diffusion and extrasynaptic transmission

2008 ◽  
pp. S89-S99
Author(s):  
L Vargová ◽  
E Syková
Keyword(s):  
Extracellular Matrix ◽  
Extracellular Space ◽  
Volume Fraction ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Diffusion Barriers ◽  
Cell Swelling ◽  
Long Distance ◽  
Diffusion Parameters ◽  
And Diffusion

The diffusion of neuroactive substances in the extracellular space (ECS) plays an important role in short- and long-distance communication between nerve cells and is the underlying mechanism of extrasynaptic (volume) transmission. The diffusion properties of the ECS are described by three parameters: 1. ECS volume fraction alpha (alpha=ECS volume/total tissue volume), 2. tortuosity lambda (lambda2=free/apparent diffusion coefficient), reflecting the presence of diffusion barriers represented by, e.g., fine neuronal and glial processes or extracellular matrix molecules and 3. nonspecific uptake k'. These diffusion parameters differ in various brain regions, and diffusion in the CNS is therefore inhomogeneous. Moreover, diffusion barriers may channel the migration of molecules in the ECS, so that diffusion is facilitated in a certain direction, i.e. diffusion in certain brain regions is anisotropic. Changes in the diffusion parameters have been found in many physiological and pathological states in which cell swelling, glial remodeling and extracellular matrix changes are key factors influencing diffusion. Changes in ECS volume, tortuosity and anisotropy significantly affect the accumulation and diffusion of neuroactive substances in the CNS and thus extrasynaptic transmission, neuron-glia communication, transmitter "spillover" and synaptic cross-talk as well as cell migration, drug delivery and treatment.

scholarly journals Cell fate coordinates mechano-osmotic forces in intestinal crypt morphogenesis

2020 ◽  
Author(s):  
Qiutan Yang ◽  
Shi-Lei Xue ◽  
Chii Jou Chan ◽  
Markus Rempfler ◽  
Dario Vischi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Single Cells ◽  
Light Sheet ◽  
Volume Reduction ◽  
Biophysical Model ◽  
Cell Swelling ◽  
Specific Cell ◽  
Light Sheet Microscopy ◽  
Lumen Volume ◽  
Sodium Glucose Cotransporter

AbstractIntestinal organoids derived from single cells undergo complex crypt-villus patterning and morphogenesis. However, the nature and coordination of the underlying forces remains poorly characterized. Through light-sheet microscopy and mechanical perturbations, we demonstrate that organoid crypt formation coincides with stark lumen volume reduction, which works synergistically with actomyosin-generated crypt apical and villus basal tension to drive morphogenesis. We analyse these mechanical features in a quantitative 3D biophysical model and detect a critical point in actomyosin tensions, above which crypt becomes robust to volume changes. Finally, via single-cell RNA sequencing and pharmacological perturbations, we show that enterocyte-specific expressed sodium/glucose cotransporter modulates lumen volume reduction via promoting cell swelling. Altogether, our study reveals how cell fate-specific changes in osmotic and actomyosin forces coordinate robust organoid morphogenesis.One Sentence SummaryEmergence of region-specific cell fates drive actomyosin patterns and luminal osmotic changes in organoid development

scholarly journals A Biophysical Model for Cytotoxic Cell Swelling

2016 ◽  
Vol 36 (47) ◽  
pp. 11881-11890 ◽  
Author(s):  
Koen Dijkstra ◽  
Jeannette Hofmeijer ◽  
Stephan A. van Gils ◽  
Michel J.A.M. van Putten
Keyword(s):  
Biophysical Model ◽  
Cell Swelling ◽  
Cytotoxic Cell

Role of cytosolic Ca in renal tubule damage induced by anoxia

1991 ◽  
Vol 260 (3) ◽  
pp. C545-C554 ◽  
Author(s):  
W. R. Jacobs ◽  
M. Sgambati ◽  
G. Gomez ◽  
P. Vilaro ◽  
M. Higdon ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Damage ◽  
Cellular Damage ◽  
Rabbit Kidney ◽  
Renal Tubules ◽  
Plasma Membrane Permeability ◽  
Fura 2 ◽  
Chemical Hypoxia ◽  
Independent Events ◽  
Energy Deprivation

Cytosolic free Ca (Caf) was measured in three different preparations of freshly prepared proximal tubules from the rabbit kidney during energy deprivation using fura-2. Isolated perfused tubules, tubules immobilized on glass cover slips, and tubules in suspension were subjected to inhibitors of oxidative phosphorylation (“chemical hypoxia”); the latter two preparations were also subjected to 40 min of anoxia. During normoxia, Caf ranged from 100 to 180 nM in all three preparations, and chemical hypoxia caused either no change or a small (30-100%) increase in Caf values. Subsequent addition of Ca ionophores increased Caf to 300-500 nM in the first 2 min and to greater than 1 microM after 15 min. In individual experiments, anoxia produced similar responses to those of chemical hypoxia, eliciting no average significant change in Caf, despite clear evidence for impaired respiration and plasma membrane damage after 40 min of anoxia. This lack of change in Caf was unrelated to “Ca buffering” by fura-2 or inactivation of the dye, since Caf increased to 666 +/- 59 nM upon addition of Ca ionophore during anoxia. These data suggest that increased Caf is not a prerequisite for cellular damage during anoxia in proximal renal tubules. Furthermore, no apparent alteration in plasma membrane permeability to Ca occurs before membrane disruption. Decreased ATP seems to initiate a series of Caf-independent events that cause irreversible injury.

NOS Inhibitors Decrease Hypoxia-induced ATP Reductions in Respiring Cerebrocortical Slices 

1999 ◽  
Vol 90 (5) ◽  
pp. 1392-1401 ◽  
Author(s):  
Lawrence Litt ◽  
Maryceline T. Espanol ◽  
Koh Hasegawa ◽  
Lee-Hong Chang ◽  
George A. Gregory ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Adenosine Triphosphate ◽  
High Performance ◽  
Brain Parenchyma ◽  
Cellular Damage ◽  
Cell Swelling ◽  
Cresyl Violet ◽  
Resonance Spectroscopy ◽  
No Production ◽  
Nos Inhibitors

Background Excess neuronal nitric oxide (NO) production might cause adenosine triphosphate loss and cellular damage in hypoxic brain parenchyma. 31P nuclear magnetic resonance spectroscopy was used to study hypoxic intracellular responses in perfused respiring cerebrocortical slices, in which NO scavenging by hemoglobin is absent, during NO synthase blockade and NO augmentation. Methods Adenosine triphosphate concentrations were monitored at 4.7 Tesla in respiring slices before, during, and after 60 min of hypoxia (oxygen tension < 5 mmHg). Slices were not treated or were pretreated with 27 microM L-nitroarginine methyl ester (L-NAME), 27 microM 7-nitroindozole (7-NI), or 27 microM L-nitroarginine. Nitrotyrosine:tyrosine ratios of slice extracts were measured using high-performance liquid chromatography. Cresyl violet-stained sections (2 microm) from random slices were examined histologically. Results After 60 min of hypoxia, adenosine triphosphate decreased to < or = 3, < or = 3, 65 +/- 6, and 25 +/- 4% of control in slices that were untreated or treated with L-nitroarginine, L-NAME, and 7-NI, respectively. After 120 min of hyperoxic recovery, adenosine triphosphate levels returned to control values in slices pretreated with L-NAME and 7-NI, but to only 30% of control in untreated or L-nitroarginine-treated slices. Nitric oxide donors administered during posthypoxic recovery partially antagonized the adenosine triphosphate recovery found with L-NAME and 7-NI. Nitric oxide synthase activity in slice homogenates, assayed via conversion of L-arginine to citrulline, was < or = 2% of control after all inhibitory treatments. The nitrotyrosine:tyrosine ratio increased by 52% in slices treated with 7-NI and by 200-300% in all other groups. Pretreatment with L-NAME and 7-NI reduced histologic evidence of cell swelling. Conclusion Neuronal NO is associated with rapid adenosine triphosphate reductions and peroxynitrite formation in acutely hypoxic cerebrocortical slices.

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