Calcium Microdomain Formation at the Perisynaptic Cradle Due to NCX Reversal: A Computational Study

Abstract

It has recently been proposed using a multi-compartmental mathematical model that negatively fixed charged membrane-associated sites constrain the flow of cations in perisynaptic astroglial processes. This restricted movement of ions between the perisynaptic cradle (PsC), principal astroglial processes and the astrocyte soma gives rise to potassium (K + ) and sodium (Na + ) microdomains at the PsC. The present paper extends the above model to demonstrate that the formation of an Na + microdomain can reverse the Na + /Ca 2+ exchanger (NCX) thus providing an additional source of calcium (Ca 2+ ) at the PsC. Results presented clearly show that reversal of the Na + /Ca 2+ exchanger is instigated by a glutamate transporter coupled increase in concentration of cytoplasmic [Na + ] i at the PsC, which and instigates Ca 2+ influx through the NCX. As the flow of Ca 2+ along the astrocyte process and away from the PsC is also constrained by Ca 2+ binding proteins, then a Ca 2+ microdomain forms at the PsC. The paper also serves to demonstrate that the EAAT, NKA, and NCX represent the minimal requirement necessary and sufficient for the development of a Ca 2+ microdomain and that these mechanisms directly link neuronal activity and glutamate release to the formation of localized Na + and Ca 2+ microdomains signals at the PsC. This local source of Ca 2+ can provide a previously underexplored form of astroglial Ca 2+ signaling.

Na+-dependent transporters: The backbone of astroglial homeostatic function

“…Experimentally, both forward and reverse mode of NCX operation in astrocytes have been documented in vitro and in situ [52][53][54][55][56][57][58]. Furthermore, NCX operating in the reverse mode in conditions of depolarisation and increased [Na + ]i may be fully sufficient to generate and maintain local Ca 2+ signal microdomains in perisynaptic astroglial processes without any need for additional activation of Ca 2+ permeable channels [59].…”

Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function

“…Here, the authors proposed that the flow of cations in small perisynaptic processes enwrapping synapses like a "cradle" is strongly restricted, giving rise to astrocytic K + and Na + microdomains close to synapses (Breslin et al, 2018). In a follow-up paper, this conception was explored further to demonstrate that local increases in [Na + ] i promote a local reversal of the NCX (Wade et al, 2019). Very small compartments may, thus, form subcellular Na + domains, also with different resting concentrations to the rest of the cell, which could in turn impact the direction of the transporter function in these areas.…”

Astrocytic Calcium Dynamics Along the Pain Pathway

“…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.…”