scholarly journals SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K+ and water

2019 ◽  
Vol 218 (12) ◽  
pp. 4017-4029 ◽  
Author(s):  
Hailun Li ◽  
Alexandra Russo ◽  
Aaron DiAntonio
Keyword(s):  
Water Transport ◽  
Neuronal Excitability ◽  
Extracellular Fluid ◽  
Signal Transduction Pathway ◽  
Extracellular Potassium ◽  
Fluid Accumulation ◽  
Water Homeostasis ◽  
Neuronal Hyperexcitability ◽  
Central Node ◽  
Transport Molecules

Glial regulation of extracellular potassium (K+) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K+ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K+ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K+ and water homeostasis in Drosophila. Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K+ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K+ and water transport molecules. This transcriptional program controls the glial capacity to regulate K+ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K+ buffering capacity of glia, which may be useful in diseases of dysregulated K+ homeostasis and hyperexcitability.

scholarly journals Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142097960
Author(s):  
Andrew S. Lapato ◽  
Sarah M. Thompson ◽  
Karen Parra ◽  
Seema K. Tiwari-Woodruff
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Regional Differences ◽  
Neuronal Excitability ◽  
Demyelinating Disease ◽  
Glutamate Uptake ◽  
Cx43 Expression ◽  
Water Homeostasis ◽  
Hippocampal Astrocytes ◽  
Multiple Sclerosis Patients

While seizure disorders are more prevalent among multiple sclerosis (MS) patients than the population overall and prognosticate earlier death & disability, their etiology remains unclear. Translational data indicate perturbed expression of astrocytic molecules contributing to homeostatic neuronal excitability, including water channels (AQP4) and synaptic glutamate transporters (EAAT2), in a mouse model of MS with seizures (MS+S). However, astrocytes in MS+S have not been examined. To assess the translational relevance of astrocyte dysfunction observed in a mouse model of MS+S, demyelinated lesion burden, astrogliosis, and astrocytic biomarkers (AQP4/EAAT2/ connexin-CX43) were evaluated by immunohistochemistry in postmortem hippocampi from MS & MS+S donors. Lesion burden was comparable in MS & MS+S cohorts, but astrogliosis was elevated in MS+S CA1 with a concomitant decrease in EAAT2 signal intensity. AQP4 signal declined in MS+S CA1 & CA3 with a loss of perivascular AQP4 in CA1. CX43 expression was increased in CA3. Together, these data suggest that hippocampal astrocytes from MS+S patients display regional differences in expression of molecules associated with glutamate buffering and water homeostasis that could exacerbate neuronal hyperexcitability. Importantly, mislocalization of CA1 perivascular AQP4 seen in MS+S is analogous to epileptic hippocampi without a history of MS, suggesting convergent pathophysiology. Furthermore, as neuropathology was concentrated in MS+S CA1, future study is warranted to determine the pathophysiology driving regional differences in glial function in the context of seizures during demyelinating disease.

scholarly journals Potassium diffusive coupling in neural networks

2010 ◽  
Vol 365 (1551) ◽  
pp. 2347-2362 ◽  
Author(s):  
Dominique M. Durand ◽  
Eun-Hyoung Park ◽  
Alicia L. Jensen
Keyword(s):  
Neural Networks ◽  
Neural Activity ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Lateral Diffusion ◽  
Normal Activity ◽  
Ionic Concentration ◽  
Extracellular Potassium ◽  
Potassium Accumulation ◽  
Diffusive Coupling

Conventional neural networks are characterized by many neurons coupled together through synapses. The activity, synchronization, plasticity and excitability of the network are then controlled by its synaptic connectivity. Neurons are surrounded by an extracellular space whereby fluctuations in specific ionic concentration can modulate neuronal excitability. Extracellular concentrations of potassium ([K + ] o ) can generate neuronal hyperexcitability. Yet, after many years of research, it is still unknown whether an elevation of potassium is the cause or the result of the generation, propagation and synchronization of epileptiform activity. An elevation of potassium in neural tissue can be characterized by dispersion (global elevation of potassium) and lateral diffusion (local spatial gradients). Both experimental and computational studies have shown that lateral diffusion is involved in the generation and the propagation of neural activity in diffusively coupled networks. Therefore, diffusion-based coupling by potassium can play an important role in neural networks and it is reviewed in four sections. Section 2 shows that potassium diffusion is responsible for the synchronization of activity across a mechanical cut in the tissue. A computer model of diffusive coupling shows that potassium diffusion can mediate communication between cells and generate abnormal and/or periodic activity in small (§3) and in large networks of cells (§4). Finally, in §5, a study of the role of extracellular potassium in the propagation of axonal signals shows that elevated potassium concentration can block the propagation of neural activity in axonal pathways. Taken together, these results indicate that potassium accumulation and diffusion can interfere with normal activity and generate abnormal activity in neural networks.

Sodium-potassium pump inhibitors increase neuronal excitability in the rat hippocampal slice: role of a Ca2+-dependent conductance

1987 ◽  
Vol 57 (2) ◽  
pp. 496-509 ◽  
Author(s):  
M. McCarren ◽  
B. E. Alger
Keyword(s):  
Hippocampal Slice ◽  
Neuronal Excitability ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Extracellular Potassium ◽  
Gamma Aminobutyric Acid ◽  
Extracellular Potassium Concentration ◽  
Spike Threshold ◽  
Pump Activity ◽  
Voltage Dependent

We have used the rat hippocampal slice preparation as a model system for studying the epileptogenic consequences of a reduction in neuronal Na+-K+ pump activity. The cardiac glycosides (CGs) strophanthidin and dihydroouabain were used to inhibit the pump. These drugs had readily reversible effects, provided they were not applied for longer than 15-20 min. Hippocampal CA1 pyramidal cells were studied with intracellular recordings; population spike responses and changes in extracellular potassium concentration ([K+]o) were also measured in some experiments. This investigation focused on the possibility that intrinsic neuronal properties are affected by Na+-K+ pump inhibitors. The CGs altered the CA1 population response evoked by an orthodromic stimulus from a single spike to an epileptiform burst. Measurements of [K+]o showed that doses of CGs sufficient to cause bursting were associated with only minor (less than 1 mM) changes in resting [K+]o. However, the rate of K+ clearance from the extracellular space was moderately slowed, confirming that a decrease in pump activity had occurred. Intracellular recording indicated that CG application resulted in a small depolarization and apparent increase in resting input resistance of CA1 neurons. Although CGs caused a decrease in fast gamma-aminobutyric acid mediated inhibitory postsynaptic potentials (IPSPs), CGs could also enhance the latter part of the epileptiform burst induced by picrotoxin, an antagonist of these IPSPs. Since intrinsic Ca2+ conductances comprise a significant part of the burst, this suggested the possibility that Na+-K+ pump inhibitors affected an intrinsic neuronal conductance. CGs decreased the threshold for activation of Ca2+ spikes (recorded in TTX and TEA) without enhancing the spikes themselves, indicating that a voltage-dependent subthreshold conductance might be involved. The action of CGs on Ca2+ spike threshold could not be mimicked by increasing [K+]o up to 10 mM. A variety of K+ conductance antagonists, including TEA, 4-AP, Ba2+ (in zero Ca2+), and carbachol were ineffective in preventing the CG-induced threshold shift of the Ca2+ spike. The shift was also seen in the presence of a choline-substituted low Na+ saline. Enhancement of a slow inward Ca2+ current is a possible mechanism for the decrease in Ca2+ spike threshold; however, it is impossible to use the Ca2+ spike as an assay when testing the effects of blocking Ca2+ conductances. Therefore, we studied the influence of CGs on the membrane current-voltage (I-V) curve, since persistent voltage-dependent conductances appear as nonlinearities in the I-V plot obtained under current clamp.(ABSTRACT TRUNCATED AT 400 WORDS)

Diurnal potassium excretory cycles in the rat

1986 ◽  
Vol 250 (5) ◽  
pp. F930-F941 ◽  
Author(s):  
L. Rabinowitz ◽  
C. J. Wydner ◽  
K. M. Smith ◽  
H. Yamauchi
Keyword(s):  
Extracellular Fluid ◽  
Potassium Content ◽  
Extracellular Potassium ◽  
Dark Phase ◽  
Adrenal Steroids ◽  
Light Phase ◽  
High Potassium ◽  
Potassium Intake ◽  
Low Levels ◽  
Adrenalectomized Rats

Diurnal potassium cycles (DPC) were measured in unanesthetized undisturbed rats fed a liquid diet and maintained in a 12-h light-dark environment. A fourfold step increase in diet potassium content increased DPC amplitude without altering phase. After presentation of the high-potassium diet, the initial adaptive increase in excretion occurred within 1.5 h (diet given during dark phase) and within 6 h (diet given during light phase). On a day when food was withheld (no potassium intake), DPC were present but with a lowered amplitude. The amount of potassium excreted on a fasting day exceeded gut and extracellular fluid potassium content and was only modestly increased when rats were previously fed a high-potassium diet. In adrenalectomized rats that received no steroid replacement or received constant infusions of low levels of aldosterone, dexamethasone, or aldosterone plus dexamethasone, potassium balance and DPC were normal. It is concluded that the amplitude of DPC in the rat is determined in part by the availability of potassium from both intracellular and extracellular potassium pools; mechanisms independent of potassium intake can generate the DPC; and the presence or the cyclic secretion of adrenal steroids is not necessary for the generation of DPC in the rat.

Role of aquaporin water channels in pleural fluid dynamics

2000 ◽  
Vol 279 (6) ◽  
pp. C1744-C1750 ◽  
Author(s):  
Yuanlin Song ◽  
Baoxue Yang ◽  
Michael A. Matthay ◽  
Tonghui Ma ◽  
A. S. Verkman
Keyword(s):  
Pleural Fluid ◽  
Water Transport ◽  
Water Channels ◽  
Pleural Space ◽  
Parietal Pleura ◽  
Pleural Effusions ◽  
Wild Type ◽  
Rt Pcr ◽  
Fluid Accumulation ◽  
Osmotic Equilibration

Continuous movement of fluid into and out of the pleural compartment occurs in normal chest physiology and in pathophysiological conditions associated with pleural effusions. RT-PCR screening and immunostaining revealed expression of water channel aquaporin-1 (AQP1) in microvascular endothelia near the visceral and parietal pleura and in mesothelial cells in visceral pleura. Comparative physiological measurements were done on wild-type vs. AQP1 null mice. Osmotically driven water transport was measured in anesthetized, mechanically ventilated mice from the kinetics of pleural fluid osmolality after instillation of 0.25 ml of hypertonic or hypotonic fluid into the pleural space. Osmotic equilibration of pleural fluid was rapid in wild-type mice (50% equilibration in <2 min) and remarkably slowed by greater than fourfold in AQP1 null mice. Small amounts of AQP3 transcript were also detected in pleura by RT-PCR, but osmotic water transport was not decreased in AQP3 null mice. In spontaneously breathing mice, the clearance of isosmolar saline instilled in the pleural space (∼4 ml · kg−1· h−1) was not affected by AQP1 deletion. In a fluid overload model produced by intraperitoneal saline administration and renal artery ligation, the accumulation of pleural fluid (∼0.035 ml/h) and was not affected by AQP1 deletion. Finally, in a thiourea toxicity model of acute endothelial injury causing pleural effusions and lung interstitial edema, pleural fluid accumulation in the first 3 h (∼4 ml · kg−1· h−1) was not affected by AQP1 deletion. These results indicate rapid osmotic equilibration across the pleural surface that is facilitated by AQP1 water channels. However, AQP1 does not appear to play a role in clinically relevant mechanisms of pleural fluid accumulation or clearance.

Intestinal nerves and ion transport: stimuli, reflexes, and responses

1985 ◽  
Vol 248 (3) ◽  
pp. G261-G271 ◽  
Author(s):  
K. A. Hubel
Keyword(s):  
Small Intestine ◽  
Ion Transport ◽  
Water Transport ◽  
Sensory Cell ◽  
Venous Blood ◽  
Extracellular Fluid ◽  
Fluid Secretion ◽  
Alkaline Secretion

The effects of extrinsic and intrinsic nerves on ion and water transport by the intestine are considered and discussed in terms of their possible physiological function. Adrenergic nerves enter the small intestine via mesenteric nerves. Adrenergic tone is usually absent in tissues in vitro but is present in vivo. The nerves increase absorption in response to homeostatic changes associated with acute depletion of extracellular fluid. Cholinergic tone that reduces fluid absorption or causes secretion has been detected in the small intestine of humans, dogs, and cats and in the colon of humans. Extrinsic cholinergic fibers generally do not affect ion transport in small intestine but probably do so in colon. Whether peptides liberated in the mucosa affect enterocytes directly is not clear. Studies on humans and rabbits suggest that the role of substance P is minor. The physiological roles of vasoactive intestinal polypeptide (VIP) and somatostatin remain to be defined. Intraluminal factors also affect ion and water transport. Mucosal rubbing, distension, and cholera toxin cause fluid secretion; acid solutions in the duodenum cause alkaline secretion; these stimuli and hypertonic glucose liberate serotonin into the lumen, the mesenteric venous blood, or both. It has been proposed that the enterochromaffin cell is an epithelial sensory cell that responds to noxious stimuli within the lumen by liberating serotonin. The serotonin initiates a neural reflex through a nicotinic ganglion to liberate a secretagogue that acts on the enterocyte. The function of VIP in this proposed reflex is unclear. The variety of intraluminal stimuli that influence epithelial function implies that there is more than one type of epithelial sensory cell (or sensory mechanism). Prostaglandins may mediate the alkaline secretion caused by acid in the duodenum. There may be other effective substances. Although it has been known for years that intraluminal stimuli affect the coordination of smooth muscle functions, it is not known whether similar stimuli also influence salt and water transport as a meal traverses the alimentary canal.

The use of bioelectrical impedance spectroscopy (BIS) to detect subclinical changes potentially associated with the development of breast cancer-related lymphedema.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 89-89
Author(s):  
Frank Vicini ◽  
Douglas W. Arthur ◽  
Maureen Lyden ◽  
Chirag Shah
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Extracellular Fluid ◽  
Bioelectrical Impedance ◽  
Locoregional Therapy ◽  
Clinical Practices ◽  
Fluid Accumulation ◽  
The Mean ◽  
Breast Cancer Related Lymphedema ◽  
Clinical Changes

89 Background: The purpose of the study was to evaluate bioelectrical impedance spectroscopy's (BIS) ability to detect and monitor extracellular fluid accumulation of the upper limb as it relates to the extent of locoregional therapy for patients with breast cancer. Methods: A total of 125 patients from 4 clinical practices, with newly diagnosed breast cancer were evaluated at baseline and following locoregional procedures that could potentially affect fluid accumulation in the arm and signal the possible development of early lymphedema. In order to assess the ability of BIS to detect sub-clinical changes by treatment modality, the change in L-Dex score from baseline to measurements taken within 180 days following surgery were calculated. Results: Fifty-one patients (40.8%) underwent lumpectomy and 74 (59.2%) mastectomy; 68 patients (54.4%) underwent sentinel lymph node (SLN) sampling. Sixty-five patients underwent radiation therapy (RT) with RT patients being more likely to have undergone lumpectomy (66.2% v. 3.2%, p<0.001) and axillary dissection (41.5% v. 19.4%, p=0.04) compared with patients not receiving RT. However, no difference in the mean number of nodes sampled (7.7 v. 5.4, p=0.14) was noted for patients receiving RT compared with those not receiving RT. Patients receiving RT had a significantly increased change in L-Dex score (0.8 v. -2.5, p=0.03) compared with those patients not receiving RT. For all patients, ALND was associated with a significantly increased change in L-Dex score (5.0 v. 0.3, p=0.003) compared with SLN. When stratifying by the number of nodes removed, a statistically significant increase in the change in L-Dex score was noted (0.4 v. 0.4 v. 4.3 v. 6.4, p=0.04) for 0-3, 4-6, 7-10, and greater than 10 lymph nodes removed. Conclusions: In this limited analysis, L-Dex scores paralleled the extent of axillary sampling and the addition of radiation therapy; these results suggest that BIS can be used to monitor patients for the early onset of edema as differences emerged within 180 days of surgery.

POTASSIUM MOVEMENTS IN RAT UTERUS STUDIED IN VITRO: I. EFFECTS OF TEMPERATURE

1963 ◽  
Vol 41 (10) ◽  
pp. 2065-2084 ◽  
Author(s):  
Edwin E. Daniel
Keyword(s):  
Extracellular Fluid ◽  
Muscle Layer ◽  
Exchange Constant ◽  
Extracellular Potassium ◽  
Longitudinal Muscle Layer ◽  
Potassium Balance ◽  
A Value ◽  
Temperature Loss ◽  
Water Accounting

1. Potassium movements have been studied in vitro in uteri of estrogenpretreated rats with42K as a tracer. At 37 °C the uterus was nearly in potassium balance in Krebs–Ringer bicarbonate and the exchange of potassium was adequately described by a single exchange constant, aside from a small fast fraction (17%) which probably contains potassium located superficially on cells as well as the extracellular potassium. No difference could be detected in their rates of exchange of potassium between two portions of the uterine horn, one containing only the longitudinal muscle layer and the other containing the remainder of the wall. The potassium exchange before or after flux correction for diffusion delay was about 5 or 9 moles cm−2sec−1, using a value of v/a of 1.8. There was a slow gain of sodium and water unrelated to potassium loss, attributed to expansion of the extracellular fluid.2. When the temperature of the Ringer fluid was reduced, the uterus remained in potassium balance at 27° and 17 °C. At 7 °C there was a net loss of potassium and exchange could no longer be described by one constant. On going from 37 to 7 °C the uterine horns shortened and the suggestion was made that muscle cells were depolarized initially by cold, or exuded water accounting for the rapidly exchanging fraction of potassium observed at this temperature. Loss of radioactive potassium from the myometrium owing to depolarization and associated with contraction appeared to account for the inhomogeneity on going to 7 °C. The Q10for influx of potassium between 27 and 7 °C was about 3 while that for efflux was about 1.6, excluding the fast fraction present at low temperatures. The Q10for efflux was diminished by depolarization and that for influx increased so that both may have been about 2. When uterine horns were stored overnight in the cold, they lost potassium and gained sodium, chloride, and water, but these ion changes were reversed on rewarming.

scholarly journals ENaCs and ASICs as therapeutic targets

2012 ◽  
Vol 302 (7) ◽  
pp. C943-C965 ◽  
Author(s):  
Yawar J. Qadri ◽  
Arun K. Rooj ◽  
Catherine M. Fuller
Keyword(s):  
Anxiety Disorders ◽  
Ion Channel ◽  
Sodium Channel ◽  
Water Transport ◽  
Therapeutic Targets ◽  
Whole Body ◽  
Cation Channels ◽  
Channel Activity ◽  
Water Homeostasis

The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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