Astrocytes: new evidence, new models, new roles.

Astrocytes have been in the limelight of active research for about 3 decades now. Over this period, ideas about their function and role in the nervous system have evolved from simple assistance in energy supply and homeostasis maintenance to a complex informational and metabolic hub that integrates data on local neuronal activity, sensory and arousal context, and orchestrates many crucial processes in the brain. Rapid progress in experimental techniques and data analysis produces a growing body of data, which can be used as a foundation for formulation of new hypotheses, building new refined mathematical models, and ultimately should lead to a new level of understanding of the contribution of astrocytes to the cognitive tasks performed by the brain. Here, we highlight recent progress in astrocyte research, which we believe expands our understanding of how low-level signaling at a cellular level builds up to processes at the level of the whole brain and animal behavior. We start our review with revisiting data on the role of noradrenaline-mediated astrocytic signaling in locomotion, arousal, sensory integration, memory, and sleep. We then briefly review astrocyte contribution to the regulation of cerebral blood flow regulation, which is followed by a discussion of biophysical mechanisms underlying astrocyte effects on different brain processes. The experimental section is closed by an overview of recent experimental techniques available for modulation and visualization of astrocyte dynamics. We then evaluate how the new data can be potentially incorporated into the new mathematical models or where and how it already has been done. Finally, we discuss an interesting prospect that astrocytes may be key players in important processes such as the switching between sleep and wakefulness and the removal of toxic metabolites from the brain milieu.

Modeling of Astrocyte Networks: Toward Realistic Topology and Dynamics.

Neuronal firing and neuron-to-neuron synaptic wiring are currently widely described as orchestrated by astrocytes-elaborately ramified glial cells tiling the cortical and hippocampal space into non-overlapping domains, each covering hundreds of individual dendrites and hundreds thousands synapses. A key component to astrocytic signaling is the dynamics of cytosolic Ca2+ which displays multiscale spatiotemporal patterns from short confined elemental Ca2+ events (puffs) to Ca2+ waves expanding through many cells. Here, we synthesize the current understanding of astrocyte morphology, coupling local synaptic activity to astrocytic Ca2+ in perisynaptic astrocytic processes and morphology-defined mechanisms of Ca2+ regulation in a distributed model. To this end, we build simplified realistic data-driven spatial network templates and compile model equations as defined by local cell morphology. The input to the model is spatially uncorrelated stochastic synaptic activity. The proposed modeling approach is validated by statistics of simulated Ca2+ transients at a single cell level. In multicellular templates we observe regular sequences of cell entrainment in Ca2+ waves, as a result of interplay between stochastic input and morphology variability between individual astrocytes. Our approach adds spatial dimension to the existing astrocyte models by employment of realistic morphology while retaining enough flexibility and scalability to be embedded in multiscale heterocellular models of neural tissue. We conclude that the proposed approach provides a useful description of neuron-driven Ca2+-activity in the astrocyte syncytium.

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

Calcium transients in thin astrocytic processes can be important in synaptic plasticity, but their mechanism is not completely understood. Clearance of synaptic glutamate leads to increase in astrocytic sodium. This can electrochemically favor the reverse mode of the Na/Ca-exchanger (NCX) and allow calcium into the cell, accounting for activity-dependent calcium transients in perisynaptic astrocytic processes. However, cytosolic sodium and calcium are also allosteric regulators of the NCX, thus adding kinetic constraints on the NCX-mediated fluxes and providing for complexity of the system dynamics. Our modeling indicates that the calcium-dependent activation and also calcium-dependent escape from the sodium-mediated inactive state of the NCX in astrocytes can form a positive feedback loop and lead to regenerative calcium influx. This can result in sodium-dependent amplification of calcium transients from nearby locations or other membrane mechanisms. Prolonged conditions of elevated sodium, for example in ischemia, can also lead to bistability in cytosolic calcium levels, where a delayed transition to the high-calcium state can be triggered by a short calcium transient. These theoretical predictions call for a dedicated experimental estimation of the kinetic parameters of the astrocytic Na/Ca-exchanger.