Modeling the heterogeneity of sodium and calcium homeostasis between cortical and hippocampal astrocytes and its impact on bioenergetics

Abstract

Emerging evidence indicates that neuronal activity-evoked changes in sodium concentration in astrocytes Naa represent a special form of excitability, which is tightly linked to all other major ions in the astrocyte and extracellular space, as well as to bioenergetics, neurotransmitter uptake, and neurovascular coupling. Recently, one of us reported that Naa transients in the neocortex have a significantly higher amplitude than those in the hippocampus. Based on the extensive data from that study, here we develop a detailed biophysical model to further understand the origin of this heterogeneity and how it affects bioenergetics in the astrocytes. In addition to closely fitting the observed experimental Naa changes under different conditions, our model shows that the heterogeneity in Naa signaling leads to substantial differences in the dynamics of astrocytic Ca2+ signals in the two brain regions, and leaves cortical astrocytes more susceptible to Na+ and Ca2+ overload under metabolic stress. The model also predicts that activity-evoked Naa transients result in significantly larger ATP consumption in cortical astrocytes than in the hippocampus. The difference in ATP consumption is mainly due to the different expression levels of NMDA receptors in the two regions. We confirm predictions from our model experimentally by fluorescence-based measurement of glutamate-induced changes in ATP levels in neocortical and hippocampal astrocytes in the absence and presence of the NMDA receptor's antagonist (2R)-amino-5-phosphonovaleric acid.

Activation of TRPV4 channels promotes the loss of cellular ATP in organotypic slices of the mouse neocortex exposed to chemical ischemia

“…These results again emphasise the relevance of glutamate‐related excitation in promoting the loss of cellular ATP (Lee et al., 1999). While astrocytes in the rodent forebrain do not express TTX‐sensitive Na v (Verkhratsky & Nedergaard, 2018), the effect of NMDA‐R inhibition on astrocytic ATP changes might have been, at least partly, caused by direct actions as neocortical astrocytes express NMDA‐R (Thapaliya et al., 2023; Verkhratsky & Nedergaard, 2018; Ziemens et al., 2019). Finally, and again in line with the important role of glutamate, inhibition of EAATs aggravated the loss of neuronal ATP.…”

Inward Operation of Sodium-Bicarbonate Cotransporter 1 Promotes Astrocytic Na+ Loading and Loss of ATP in Mouse Neocortex during Brief Chemical Ischemia

“…We build on our previous work, where we modeled dynamic changes in astrocytic Na + , K + , Cl − , and Ca 2+ concentrations [45,46] by incorporating the main pathways regulating intra-and extracellular pH (pH i and pH o , respectively). The equations for intra-and extracellular Na + concentrations ([Na + ] i and [Na + ] o , respectively) are modified accordingly.…”