Astrocytic modulation of neuronal excitability through K + spatial buffering

Bellot-Saez, Alba; Kékesi, Orsolya; Morley, John W.; Buskila, Yossi

doi:10.1016/j.neubiorev.2017.03.002

Cited by 191 publications

(200 citation statements)

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“…Astrocytes in the normal CNS are coupled by gap junctions, containing two of the members of the connexin family, Cx30 and Cx43. The junctions allow the passage of water and ions, particularly potassium and other small molecules, thus distributing these elements from an area of focal increase to widespread areas (spatial buffering) . The loss of both connexins, Cx43 and Cx30, in astrocytes of a mouse model leads to dysmyelination .…”

Section: Murine Models Of Axdmentioning

confidence: 99%

Alexander disease: an astrocytopathy that produces a leukodystrophy

2018

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Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in the CNS do not express GFAP, AxD is a primary astrocyte disease. Astrocytes acquire a large number of pathological features, including changes in morphology, the loss or diminution of a number of critical astrocyte functions and the activation of cell stress and inflammatory pathways. AxD is also characterized by white matter degeneration, a pathology that has led it to be included in the "leukodystrophies." Furthermore, variable degrees of neuronal loss take place. Thus, the astrocyte pathology triggers alterations in other cell types. Here, we will review the neuropathology of AxD and discuss how a disease of astrocytes can lead to severe pathologies in non-astrocytic cells. Our knowledge of the pathophysiology of AxD will also lead to a better understanding of how astrocytes interact with other CNS cells and how astrocytes in the gliosis that accompanies many neurological disorders can damage the function and survival of other cells.

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Section: Murine Models Of Axdmentioning

confidence: 99%

Alexander disease: an astrocytopathy that produces a leukodystrophy

2018

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“…Changes in extracellular potassium ([K + ] e ) concentration modulate neuronal networks via membrane depolarization/hyperpolarization with subsequent activation/inactivation of voltage‐gated channels and alteration to transmission at the synapse (Bellot‐Saez, Kekesi, Morley, & Buskila, ; Kofuji & Newman, ; Larsen, Stoica, & MacAulay, ; Sibille, Dao Duc, Holcman, & Rouach, ; Sibille, Pannasch, & Rouach, ). Limited extracellular space in the central nervous system increases potential for small changes in [K + ] e to have a significant impact on neuronal activity.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is crucial to clear potassium rapidly and efficiently. It is now widely accepted that activity‐induced changes in [K + ] e are rapidly managed by the astrocytic potassium inward rectifying channel subtype 4.1 (Kir4.1) (Bellot‐Saez et al, ; Butt & Kalsi, ; Chever, Djukic, McCarthy, & Amzica, ; D'Ambrosio, Gordon, & Winn, ; Larsen et al, ; Larsen & MacAulay, ; Sibille et al, ) and the astrocyte‐specific α2β2 isoform of the Na + /K + ‐ATPase (NKA) (D'Ambrosio et al, ; Larsen et al, ; Pellerin & Magistretti, ; Stoica et al, ). Due to the highly negative resting membrane potential of astrocytes, Kir4.1 is highly responsive to increases in [K + ] e with local inward K + uptake into astrocytes (Sibille et al, , ) whereas the astrocyte‐specific NKA is additionally responsive to changes in intracellular Na + driven by the synapse‐dependent glutamate transporter (Larsen, Holm, Vilsen, & MacAulay, ; Larsen, Stoica, et al, ; Pellerin & Magistretti, ) and/or the Na + /Ca 2+ exchanger in response to astrocyte Ca 2+ transients (Wang, Smith, et al, ).…”

Section: Introductionmentioning

confidence: 99%

Serotonin, norepinephrine, and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

Wotton

Cross

Bekar

2020

J of Neuroscience Research

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Changes in extracellular potassium ([K+]e) modulate neuronal networks via changes in membrane potential, voltage‐gated channel activity, and alteration to transmission at the synapse. Given the limited extracellular space in the central nervous system, potassium clearance is crucial. As activity‐induced potassium transients are rapidly managed by astrocytic Kir4.1 and astrocyte‐specific Na+/K+‐ATPase, any neurotransmitter/neuromodulator that can regulate their function may have indirect influence on network activity. Neuromodulators differentially affect cortical/thalamic networks to align sensory processing with differing behavioral states. Given serotonin (5HT), norepinephrine (NE), and acetylcholine (ACh) differentially affect spike frequency adaptation and signal fidelity (“signal‐to‐noise”) in somatosensory cortex, we hypothesize that [K+]e may be differentially regulated by the different neuromodulators to exert their individual effects on network function. This study aimed to compare effects of individually applied 5HT, NE, and ACh on regulating [K+]e in connection to effects on cortical‐evoked response amplitude and adaptation in male mice. Using extracellular field and K+ ion‐selective recordings of somatosensory stimulation, we found that differential effects of 5HT, NE, and ACh on [K+]e regulation mirrored differential effects on amplitude and adaptation. 5HT effects on transient K+ recovery, adaptation, and field post‐synaptic potential amplitude were disrupted by barium (200 µM), whereas NE and ACh effects were disrupted by ouabain (1 µM) or iodoacetate (100 µM). Considering the impact [K+]e can have on many network functions; it seems highly efficient that neuromodulators regulate [K+]e to exert their many effects. This study provides functional significance for astrocyte‐mediated buffering of [K+]e in neuromodulator‐mediated shaping of cortical network activity.

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“…To test this prediction experimentally, we increased [K + ] o from 2 mM to 5 mM. Such changes of [K + ] o occur in physiological range (Bellot‐Saez et al, ). Indeed, we observed an increase in the frequency of Ca 2+ events in thin astrocytic processes (the effect of HW: F (19,160) = 20.67, p < .0001; the effect of [K + ] o : F (1,160) = 8.863, p = .0034; interaction: F (19,160) = 2.568, p = .0007; n = 9, two‐way RM ANOVA; Figure c–e) but no significant increase in the active range of HWs ( p = .88, n = 9, Wilcoxon signed‐rank test).…”

Section: Resultsmentioning

confidence: 99%

“…Besides [Ca 2+ ] o , another parameter that determines the transmembrane Ca 2+ flow is the Ca 2+ conductance of astrocytic plasma membrane. When neuronal network activity is high, activity‐dependent changes in extracellular K + concentration can depolarize the astrocyte and increase the open probability of VGCCs (Bellot‐Saez, Kekesi, Morley, & Buskila, ; Duffy & MacVicar, ). Therefore, we simulated how changes in membrane potential ( V m ) can affect the frequency of Ca 2+ events in the processes of different diameter.…”

Section: Resultsmentioning

confidence: 99%

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Gordleeva²,

Tang

et al. 2018

Glia

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Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface‐to‐volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+‐induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5‐trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage‐gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

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Astrocytic modulation of neuronal excitability through K + spatial buffering

Cited by 191 publications

References 125 publications

Alexander disease: an astrocytopathy that produces a leukodystrophy

Alexander disease: an astrocytopathy that produces a leukodystrophy

Serotonin, norepinephrine, and acetylcholine differentially affect astrocytic potassium clearance to modulate somatosensory signaling in male mice

Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

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