Glial modulation of neural excitability mediated by extracellular pH: a hypothesis revisited

doi:10.1016/S0079-6123(00)25012-7

Progress in Brain Research

Volume 125, 2000, Pages 217-228

https://doi.org/10.1016/S0079-6123(00)25012-7 Get rights and content

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This chapter discusses an update on a model interaction between astrocytes and neurons based on activity-induced changes in extracellular ion concentrations, K ⁺ and H ⁺, mainly, the nature of the astrocyte-induced extracellular acidification, and the manner in which pH changes can alter neural excitability. The proposed interaction represented an example of volume transmission mediated by ions. It was viewed as a negative feedback loop whereby active neurons would signal to nearby astrocytes the extent of their current activity, in the form of graded changes in extracellular K⁺ concentration, and astrocytes would respond by producing graded degrees of extracellular acidification. The acidification would, in turn, dampen neuronal excitability. It is argued that this feedback system could function to adjust local brain excitability in relationship to ongoing activity; the more intense the activity, the greater the resulting acidification and reduction in excitability.

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Despite the molecular evidence that a nearly linear steady-state current-voltage relationship in mammalian astrocytes reflects a total current resulting from more than one differentially regulated K⁺ conductance, detailed ordinary differential equation (ODE) models of membrane voltage V_m are still lacking. Various experimental results reporting altered rectification of the major Kir currents in glia, dominated by Kir4.1, have motivated us to develop a detailed model of V_m dynamics incorporating the weaker potassium K2P-TREK1 current in addition to Kir4.1, and study the stability of the resting state V_r. The main question is whether, with the loss of monotonicity in glial I-V curve resulting from altered Kir rectification, the nominal resting state V_r remains stable, and the cell retains the trivial, potassium electrode behavior with V_m after E_K. The minimal two-dimensional model of V_m near V_r showed that an N-shape deformed Kir I-V curve induces multistability of V_m in a model that incorporates K2P activation kinetics, and nonspecific K⁺ leak currents. More specifically, an asymmetrical, nonlinear decrease of outward Kir4.1 conductance, turning the channels into inward rectifiers, introduces instability of V_r. That happens through a robust bifurcation giving birth to a second, more depolarized stable resting state V_dr > −10 mV. Realistic recordings from electrographic seizures were used to perturb the model. Simulations of the model perturbed by constant current through gap junctions and seizure-like discharges as local field potentials led to depolarization and switching of V_m between the two stable states, in a downstate-upstate manner. In the event of prolonged depolarizations near V_dr, such catastrophic instability would affect all aspects of the glial function, from metabolic support to membrane transport, and practically all neuromodulatory roles assigned to glia.
Challenges and opportunities of advanced gliomodulation technologies for excitation-inhibition balance of brain networks
2021, Current Opinion in Biotechnology
Citation Excerpt :
Overall, modulation of oligodendrocytes with available neural technologies may regulate excitatory and inhibitory networks that contribute to both gross and fine-tuning of behaviors. Although the concept of glial modulation and gliomodulation have existed for decades [36,45••,60–63], technological limitations have impeded advancements in scientific knowledge. In contrast to neural activity which can be easily detected or evoked with an electrode, glial activity has been much more difficult to detect and manipulate [11].
Neocortical in vivo focal and spreading potassium responses and the influence of astrocytic gap junctional coupling
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Potassium spatial buffering is known to be one of the mechanisms responsible for K+ regulation and distribution in the brain. It was proposed that astrocytic gap junctional coupling has a role in extracellular potassium ion concentration ([K+]o) buffering (Orkand et al., 1966; Ransom, 2000), although measurements of electrolyte and extracellular space volume changes could be only partly explained by spatial buffering currents (Dietzel et al., 1989). Wallraff et al. (2006) showed that gap junction-mediated currents represented only about 30% of whole-cell currents in wildtype astrocytes in hippocampal slices.
Raised extracellular potassium ion (K⁺) concentration is associated with several disorders including migraine, stroke, neurotrauma and epilepsy. K⁺ spatial buffering is a well-known mechanism for extracellular K⁺ regulation/distribution. Astrocytic gap junction-mediated buffering is a controversial candidate for K⁺ spatial buffering. To further investigate the existence of a K⁺ spatial buffering and to assess the involvement of astrocytic gap junctional coupling in K⁺ redistribution, we hypothesized that neocortical K⁺ and concomitant spreading depolarization (SD)-like responses are controlled by powerful local K⁺ buffering mechanisms and that K⁺ buffering/redistribution occurs partially through gap junctional coupling. Herein, we show, in vivo, that a threshold amount of focally applied KCl is required to trigger local and/or distal K⁺ responses, accompanied by a SD-like response. This observation indicates the presence of powerful local K⁺ buffering which mediates a rapid return of extracellular K⁺ to the baseline. Application of gap junctional blockers, carbenoxolone and Gap27, partially modulated the amplitude and shape of the K⁺ response and noticeably decreased the velocity of the spreading K⁺ and SD-like responses. Opening of gap junctions by trimethylamine, slightly decreased the amplitude of the K⁺ response and markedly increased the velocity of redistribution of K⁺ and SD-like events. We conclude that spreading K⁺ responses reflect powerful local K⁺ buffering mechanisms which are partially modulated by gap junctional communication. Gap junctional coupling mainly affected the velocity of the K⁺ and SD-like responses.
Changes in extracellular ionic composition
2016, The Curated Reference Collection in Neuroscience and Biobehavioral Psychology
Ion gradients, formed by the relative concentrations of ions in the extra- and intracellular spaces, form the basis of neuronal function. The gradients are generated by electrogenic pumps and are maintained by control of ion channel function. During seizure activity, there is an increase in extracellular potassium and a decrease in calcium, magnesium, sodium, and chloride. These levels are then brought back to ‘baseline’ levels after termination of the seizure activity. Both neuronal and glial mechanisms contribute to the regulation of the ionic environment and to the restoration of the ion gradients after seizures. Whether abnormalities in this regulation are a cause of seizures is not known.
Effects of acute hypoxia/acidosis on intracellular pH in differentiating neural progenitor cells
2012, Brain Research
Citation Excerpt :
The inner layer of cells responded with an intracellular acidification to hypoxia. Hypoxia has been shown to induce pHi decrease in brain cells, in particular astrocytes, and it has been hypothesized that astroglial cells play critical roles in neuronal development and the fine tuning of the microenvironment in the brain (Bondarenko and Chesler, 2001; Fujiwara et al., 1992; Ransom, 2000). In line with this, we found that hypoxic treatment specifically induced a decrease in resting pHi in the inner migrating cells.
The response of differentiating mouse neural progenitor cells, migrating out from neurospheres, to conditions simulating ischemia (hypoxia and extracellular or intracellular acidosis) was studied. We show here, by using BCECF and single cell imaging to monitor intracellular pH (pH_i), that two main populations can be distinguished by exposing migrating neural progenitor cells to low extracellular pH or by performing an acidifying ammonium prepulse. The cells dominating at the periphery of the neurosphere culture, which were positive for neuron specific markers MAP-2, calbindin and NeuN had lower initial resting pH_i and could also easily be further acidified by lowering the extracellular pH. Moreover, in this population, a more profound acidification was seen when the cells were acidified using the ammonium prepulse technique. However, when the cell population was exposed to depolarizing potassium concentrations no alterations in pH_i took place in this population. In contrast, depolarization caused an increase in pH_i (by 0.5 pH units) in the cell population closer to the neurosphere body, which region was positive for the radial cell marker (GLAST). This cell population, having higher resting pH_i (pH 6.9–7.1) also responded to acute hypoxia. During hypoxic treatment the resting pH_i decreased by 0.1 pH units and recovered rapidly after reoxygenation. Our results show that migrating neural progenitor cells are highly sensitive to extracellular acidosis and that irreversible damage becomes evident at pH 6.2. Moreover, our results show that a response to acidosis clearly distinguishes two individual cell populations probably representing neuronal and radial cells.
Cellular bases of focal and generalized epilepsies
2012, Handbook of Clinical Neurology
This chapter summarizes many of the cellular alterations that give rise to an imbalance between excitation and inhibition, and to a hypersynchronous neuronal discharge. Contributing intrinsic neuronal properties include aberrant channel function and/or location that may cause excessive discharge and/or inadequate hyperpolarization of excitatory (projection) cells or loss of inhibition resulting from changes (damage to) inhibitory interneurons. Altered/abnormal synaptic function may also be critical, such as activity-dependent changes in receptor properties and/or plasticity of synaptic connectivity; such changes may affect both excitatory (e.g., mediated by glutamatergic synapses) and inhibitory (e.g., local GABA circuits) function. Finally, dysfunction of extracellular influences, such as those mediated by glial activities, changes in extracellular spaces, effects of hormonal modulators, and dependent on an intact vascular system, can result in hyperexcitability and seizures discharge. These cellular changes can result from genetic disorders, from aberrant developmental programs, or from trauma-induced brain injury. The net effect of these changes – often multiple and complex – can lead to a focal epilepsy such as temporal lobe epilepsy (if the abnormalities are restricted to temporal lobe structures) or to a more generalized phenotype (e.g., generalized epilepsy with febrile seizures plus, GEFS +). Insight into underlying cellular and molecular abnormalities of a given epilepsy phenotype will, we hope, lead to better and earlier treatments.

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III. Glia-neuronal signaling Chapter 10Glial modulation of neural excitability mediated by extracellular pH: a hypothesis revisited

Publisher Summary

Prog. Neurobiol.

J. Neurosci. Meth.

Neuron

Prog. Neurobiol.

Brain Res.

Neuroscience

Neuroscience

Brain Res.

Prog. Neurobiol.

Brain Res.

Brain Res.

Concentration of carbon dioxide, interstitial pH and synaptic transmission in hippocampal formation of the rat

J. Physiol (Lond.)

Ion activities and potassium uptake mechanisms of glial cells in guinea-pig olfactory cortex slices

J. Physiol. (Lond.)

pH regulation in mammalian neurons

Intracellular pH as a regulatory signal in astrocyte metabolism

Glia

K+-induced alkalinization in mouse cerebral astrocytes mediated by reversal of electrogenic Na+-HCO3− cotransport

Am. J. Physiol.

Regional variation in stimulated extracellular pH transients in the mammalian CNS

Soc. Neurosci. Abstr.

Intracellular pH of astrocytes increases rapidly with cortical stimulation

Am. J. Physiol.

Intracellular pH transients of mammalian astrocytes

J. Neurosci.

Electrophysiological properties of rat CA1 pyramidal neurones in vitro modified by changes in extracellular bicarbonate

J. Physiol. (Lond.)

Changes in glial K+ currents with decreased extracellular volume in developing rat white matter

J. Neurosci. Res.

Free concentrations of Na, K, and Cl in the retina of the honeybee drone: stimulus-induced redistribution and homeostasis

Ann. NY Acad. Sci.

Activity-dependent K+ accumulation in the developing rat optic nerve

Science

pH Regulation in Invertebrate Glia

The after-effects of impulses in the giant nerve fibers of Loligo

J. Physiol. (Lond.)

Endogenous H/+ modulation of NMDA receptor-mediated EPSCs revealed by carbonic anhydrase inhibition in rat hippocampus

J. Physiol. (Lond.)

Energy metabolism at the cellular level of the CNS

Can. J. Physiol. Pharmacol.

Activity-evoked changes in extracellular pH

pH and Brain Function

Cell structure and function in the visual cortex of the cat

J. Physiol. (Lond.)

Neuroglia

III. Glia-neuronal signaling Chapter 10
Glial modulation of neural excitability mediated by extracellular pH: a hypothesis revisited

K⁺-induced alkalinization in mouse cerebral astrocytes mediated by reversal of electrogenic Na⁺-HCO₃⁻ cotransport

Changes in glial K⁺ currents with decreased extracellular volume in developing rat white matter

Activity-dependent K⁺ accumulation in the developing rat optic nerve

Endogenous H^/+ modulation of NMDA receptor-mediated EPSCs revealed by carbonic anhydrase inhibition in rat hippocampus