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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 ∼50% 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.SIGNIFICANCE STATEMENTAstrocyte 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.

Astrocytes express glutamate transporters at high density at perisynaptic processes which can tightly control extracellular glutamate levels in proximity of postsynaptic receptors with the potential to modulate functional neuronal activity. Glutamate uptake by these transporters also closely depends on activity-dependent extracellular ion concentrations and may also be regulated by the astrocyte’s intracellular calcium. On the other hand, intracellular \(\mathrm{Ca}^{2+}\) dynamics in the astrocyte too can be modulated by glutamate uptake, with potential for functionally relevant interactions with neural activity. Here, we introduce original modeling arguments to study functional implications of glutamate uptake by astrocytes both on their physiology and on that of neurons. In the first case, we consider the contribution of \(\mathrm{{Na^+}}\) and \(\mathrm{{K^+}}\) homeostasis to astrocytic glutamate uptake, revealing that intracellular anisotropy could account for spatial segregation of transporter- versus receptor-mediated calcium signaling pathways. In the second case, we study how regulation of extracellular glutamate levels by astrocytic transporters could affect tuning responses of primary sensory areas, linking our analysis to experimental observations in the ferret’s primary visual cortex by Schummers et al. (2008, Science 320:1638). We conclude that glutamate uptake by astrocytes can modulate function of neuronal circuits in multiple ways that may look subtle at individual synaptic contacts, but at network level, lead instead to functionally relevant changes in neuronal tuning and stimulus discrimination.

International audience; The idea that astrocytes may be active partners in synaptic information processing has recently emerged from abundant experimental reports. Because of their spatial proximity to neurons and their bidirectional communication with them, astrocytes are now considered as an important third element of the synapse. Astrocytes integrate and process synaptic information and by doing so generate cytosolic calcium signals that are believed to reflect neuronal transmitter release. Moreover, they regulate neuronal information transmission by releasing gliotransmitters into the synaptic cleft affecting both pre-and postsynaptic receptors. Concurrent with the first experimental reports of the astrocytic impact on neural network dynamics, computational models describing astrocytic functions have been developed. In this review, we give an overview over the published computational models of astrocytic functions, from single-cell dynamics to the tripartite synapse level and network models of astrocytes and neurons.

Astrocytes integrate and process synaptic information and exhibit calcium (Ca2+) signals in response to incoming information from neighboring synapses. The generation of Ca2+ signals is mostly attributed to Ca2+ release from internal Ca2+ stores evoked by an elevated metabotropic glutamate receptor (mGluR) activity. Different experimental results associated the generation of Ca2+ signals to the activity of the glutamate transporter (GluT). The GluT itself does not influence the intracellular Ca2+ concentration, but it indirectly activates Ca2+ entry over the membrane. A closer look into Ca2+ signaling in different astrocytic compartments revealed a spatial separation of those two pathways. Ca2+ signals in the soma are mainly generated by Ca2+ release from internal Ca2+ stores (mGluR-dependent pathway). In astrocytic compartments close to the synapse most Ca2+ signals are evoked by Ca2+ entry over the plasma membrane (GluT-dependent pathway). This assumption is supported by the finding, that the volume ratio between the internal Ca2+ store and the intracellular space decreases from the soma towards the synapse. We extended a model for mGluR-dependent Ca2+ signals in astrocytes with the GluT-dependent pathway. Additionally, we included the volume ratio between the internal Ca2+ store and the intracellular compartment into the model in order to analyze Ca2+ signals either in the soma or close to the synapse. Our model results confirm the spatial separation of the mGluR- and GluT-dependent pathways along the astrocytic process. The model allows to study the binary Ca2+ response during a block of either of both pathways. Moreover, the model contributes to a better understanding of the impact of channel densities on the interaction of both pathways and on the Ca2+ signal., Author summary Astrocytes are considered as active partners in neural information processing, because they integrate and process synaptic information and control synaptic transmission. Neuronal transmitter release induces the generation of Ca2+ signals in astrocytes. The functional role of astrocytic Ca2+ signals is still under debate. However, experimental results were able to show that astrocytic Ca2+ signaling acts to control local network activity, which plays an important role in diseases like epilepsy. Thus, it is of special interest to investigate the underlying mechanisms for Ca2+ signals in astrocytes in order to understand the role of astrocytes in neural network activity. Two different mechanisms are known to be responsible for the generation of Ca2+ signals in astrocytes. These mechanisms are the release of Ca2+ from internal Ca2+ stores and the entry of Ca2+ through the plasma membrane. We studied the interaction of those two different mechanisms for the generation of Ca2+ signals and found that these mechanisms are spatially separated along the astrocytic processes.