Sodium–Calcium Exchanger Can Account for Regenerative Ca2+ Entry in Thin Astrocyte Processes

Brazhe, Alexey; Verisokin, Andrey Yu.; Verveyko, Darya V.; Postnov, Dmitry E.

doi:10.3389/fncel.2018.00250

Cited by 36 publications

(23 citation statements)

References 31 publications

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“…8). The transport direction of NCX, however, can reverse in response to increases in intracellular sodium and calcium concentrations, thereby mediating calcium import Fern et al, 2014;Boddum et al, 2016;Boscia et al, 2016;Parpura et al, 2016;Brazhe et al, 2018;Gerkau et al, 2018).…”

Section: Reverse Ncx Contributes To Local Calcium Signaling In Neocormentioning

confidence: 99%

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

et al. 2019

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Activity-related sodium transients induced by glutamate uptake represent a special form of astrocyte excitability. Astrocytes of the neocortex, as opposed to the hippocampus proper, also express ionotropic glutamate receptors, which might provide additional sodium influx. We compared glutamate-related sodium transients in astrocytes and neurons in slices of the neocortex and hippocampus of juvenile mice of both sexes, using widefield and multiphoton imaging. Stimulation of glutamatergic afferents or glutamate application induced sodium transients that were twice as large in neocortical as in hippocampal astrocytes, despite similar neuronal responses. Astrocyte sodium transients were reduced by ϳ50% upon blocking NMDA receptors in the neocortex, but not hippocampus. Neocortical, but not hippocampal, astrocytes exhibited marked sodium increases in response to NMDA. These key differences in sodium signaling were also observed in neonates and in adults. NMDA application evoked local calcium transients in processes of neocortical astrocytes, which were dampened upon blocking sodium/calcium exchange (NCX) with KB-R7943 or SEA0400. Mathematical computation based on our data predict that NMDA-induced sodium increases drive the NCX into reverse mode, resulting in calcium influx. Together, our study reveals a considerable regional heterogeneity in astrocyte sodium transients, which persists throughout postnatal development. Neocortical astrocytes respond with much larger sodium elevations to glutamatergic activity than hippocampal astrocytes. Moreover, neocortical astrocytes experience NMDA-receptor-mediated sodium influx, which hippocampal astrocytes lack, and which drives calcium import through reverse NCX. This pathway thereby links sodium to calcium signaling and represents a new mechanism for the generation of local calcium influx in neocortical astrocytes.Astrocyte calcium signals play a central role in neuron-glia interaction. Moreover, activity-related sodium transients may represent a new form of astrocyte excitability. Here we show that activation of NMDA receptors results in prominent sodium transients in neocortical, but not hippocampal, astrocytes in the mouse brain. NMDA receptor activation is accompanied by local calcium signaling in processes of neocortical astrocytes, which is augmented by sodium-driven reversal of the sodium/calcium exchanger. Our data demonstrate a significant regional heterogeneity in the magnitude and mechanisms of astrocyte sodium transients. They also suggest a close interrelation between NMDA-receptor-mediated sodium influx and calcium signaling through the reversal of sodium/ calcium exchanger, thereby establishing a new pathway for the generation of local calcium signaling in astrocyte processes.

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Section: Reverse Ncx Contributes To Local Calcium Signaling In Neocormentioning

confidence: 99%

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

et al. 2019

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“…Such sparks may not be detectable in our experimental conditions (resolution and speed of imaging) but still could play a role in astrocyte physiology, for example, trigger local release of gliotransmitters. A recent computational study has also suggested that local Ca 2+ sparks can be amplified through NCX (Brazhe et al, ). Moreover, Ca 2+ sparks in ER/mitochondria‐free leaflets can potentially integrate to trigger spreading Ca 2+ events in their parent astrocytic branches containing the Ca 2+ stores.…”

Section: Discussionmentioning

confidence: 99%

“…However, the Ca 2+ entry through the VGCCs may still need to be amplified by CICR (Carmignoto, Pasti, & Pozzan, 1998). Na + /Ca 2+ exchanger (NCX) can transport Ca 2+ into the astrocytes upon increase in intracellular Na + concentration which occurs during glutamate uptake (Brazhe, Verisokin, Verveyko, & Postnov, 2018;Oschmann, Mergenthaler, Jungnickel, & Obermayer, 2017;Rojas et al, 2007). Other sources of the Ca 2+ entry in astrocytes include store-operated channels ORAI1 and transient receptor potential type A channels (TRPAs) (Bazargani & Attwell, 2016;Shigetomi, Jackson-Weaver, Huckstepp, O'Dell, & Khakh, 2013).…”

mentioning

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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“…NCX usually works in a forward mode, extruding Ca 2+ and transporting Na + into the cell. When intracellular Na + concentration increases, NCX extrudes Na + and brings Ca 2+ in Brazhe et al (2018) and Wade et al (2019). Several mechanisms are reported to increase intracellular Na + concentration in astrocytes.…”

Section: Source Of Calcium In Astrocytesmentioning

confidence: 99%

Astrocytic Calcium Dynamics Along the Pain Pathway

Cho

Huh

2020

Front. Cell. Neurosci.

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Astrocytes, once thought to be passive cells merely filling the space between neurons in the nervous system, are receiving attention as active modulators of the brain and spinal cord physiology by providing nutrients, maintaining homeostasis, and modulating synaptic transmission. Accumulating evidence indicates that astrocytes are critically involved in chronic pain regulation. Injury induces astrocytes to become reactive, and recent studies suggest that reactive astrocytes can have either neuroprotective or neurodegenerative effects. While the exact mechanisms underlying the transition from resting astrocytes to reactive astrocytes remain unknown, astrocytic calcium increase, coordinated by inflammatory molecules, has been suggested to trigger this transition. In this mini review article, we will discuss the roles of astrocytic calcium, channels contributing to calcium dynamics in astrocytes, astrocyte activations along the pain pathway, and possible relationships between astrocytic calcium dynamics and chronic pain.

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Sodium–Calcium Exchanger Can Account for Regenerative Ca2+ Entry in Thin Astrocyte Processes

Cited by 36 publications

References 31 publications

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

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

Astrocytic Calcium Dynamics Along the Pain Pathway

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