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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.

The term “memory strength” generally refers to how well one remembers something but more precisely it contains multiple modalities, such as how easily, how accurately, how confidently and how vividly we remember it. In human, these modalities of memory strength are dissociable. In this study, we asked whether we can isolate a behavioral component that is dissociable from others in hippocampus-dependent memory tasks in mice, which potentially reflect a modality of memory strength. Using a virus-mediated inducible method, we ablated immature neurons in the dentate gyrus in mice after we trained the mice with hippocampus-dependent memory tasks normally. In memory retrieval tests, these ablated mice initially show intact performance. However, the ablated mice ceased learned behavior prematurely within a trial compared with control mice. In addition, the ablated mice showed shorter duration of individual episodes of learned behavior. Both affected behavioral measurements point to persistence of learned behavior. Thus, the effect of the post-learning manipulation showed dissociation between initial performance and persistence of learned behavior. These two behavioral components are likely to reflect different brain functions and be mediated by separate mechanisms, which might represent different modalities of memory strength. These simple dissociable measurements in widely used behavioral paradigms would be useful to understand detailed mechanisms underlying the expression of learned behavior and potentially different modalities of memory strength in mice. We also discuss a potential role that immature neurons in the dentate gyrus may play in persistence of learned behavior. Significance statement We use the term “memory strength” both in everyday life and research settings. Memory strength generally means how well we remember something. However, depending on context, its meaning is varied; it can mean how easily, accurately, vividly and/or confidently we remember it. These different modalities of memory strength are generally correlated but is known to be partly independent. In this study, we asked whether such independent or dissociable behavioral components exist in hippocampus-dependent memory tasks in mice. We provide evidence that initial performance and persistence of learned behavior during memory retrieval tests are dissociable in three memory tasks. Such dissociable components would be helpful to study different modalities of memory strength and their underlying mechanisms in mice in future studies.

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.