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Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions. Indeed, abnormal astrocytic signaling can cause or contribute to synaptic and network imbalances, leading to cognitive impairment. We discuss evidence for this from animal models of Alzheimer’s disease and multiple sclerosis and from animal studies of sleep deprivation and drug abuse and addiction. Understanding the emerging roles of astrocytes in cognitive function and dysfunction will open up a large array of new therapeutic opportunities.Volterra et al. review evidence that astrocyte-generated signals participate in recruitment and function of neuronal networks underlying memory performance and that signal abnormalities under pathological conditions contribute to cognitive impairment.

The authors characterize the endogenous local calcium dynamics in the processes of adult mouse hippocampal astrocytes, and find that the astrocytic Ca 2+ activity is generated by synaptic events and contributes to basal synaptic transmission reliability. Astrocytes communicate with synapses by means of intracellular calcium ([Ca 2+ ] i ) elevations, but local calcium dynamics in astrocytic processes have never been thoroughly investigated. By taking advantage of high-resolution two-photon microscopy, we identify the characteristics of local astrocyte calcium activity in the adult mouse hippocampus. Astrocytic processes showed intense activity, triggered by physiological transmission at neighboring synapses. They encoded synchronous synaptic events generated by sparse action potentials into robust regional (∼12 μm) [Ca 2+ ] i elevations. Unexpectedly, they also sensed spontaneous synaptic events, producing highly confined (∼4 μm), fast (millisecond-scale) miniature Ca 2+ responses. This Ca 2+ activity in astrocytic processes is generated through GTP- and inositol-1,4,5-trisphosphate–dependent signaling and is relevant for basal synaptic function. Thus, buffering astrocyte [Ca 2+ ] i or blocking a receptor mediating local astrocyte Ca 2+ signals decreased synaptic transmission reliability in minimal stimulation experiments. These data provide direct evidence that astrocytes are integrated in local synaptic functioning in adult brain.

Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss‐of‐function mutations in α 2 Na + ,K + ATPase (α 2 NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression (CSD), the phenomenon that underlies migraine aura and activates migraine headache mechanisms, is facilitated in heterozygous FHM2‐knockin mice with reduced expression of α 2 NKA. The mechanisms underlying an increased susceptibility to CSD in FHM2 are unknown. Here, we show reduced rates of glutamate and K + clearance by cortical astrocytes during neuronal activity and reduced density of GLT‐1a glutamate transporters in cortical perisynaptic astrocytic processes in heterozygous FHM2‐knockin mice, demonstrating key physiological roles of α 2 NKA and supporting tight coupling with GLT‐1a. Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters in wild‐type mice, we obtain evidence that defective glutamate clearance can account for most of the facilitation of CSD initiation in FHM2‐knockin mice, pointing to excessive glutamatergic transmission as a key mechanism underlying the vulnerability to CSD ignition in migraine. Synopsis FHM2 is a rare monogenic form of migraine with aura caused by loss‐of‐function mutations in the astrocytic α2 Na,K ATPase. Investigating the mechanisms underlying the facilitation of cortical spreading depression (CSD) in a genetic mouse model of FHM2 uncovers insights into migraine pathophysiology. The rates of clearance of glutamate and K + released during cortical activity are both reduced in heterozygous FHM2‐knockin mice with 50% reduced expression of the α2 Na,K ATPase (NKA). In FHM2‐knockin mice, the membrane density of the glutamate transporter GLT‐1 is about 50% reduced in astrocytic processes surrounding cortical excitatory synapses, but is unaltered in axon terminals. The relative impairment of glutamate clearance in FHM2‐knockin mice is activity dependent. Most of the facilitation of CSD initiation and a large fraction of the facilitation of CSD propagation in FHM2‐knockin mice are due to the defective glutamate clearance by cortical astrocytes. Graphical Abstract FHM2 is a rare monogenic form of migraine with aura caused by loss‐of‐function mutations in the astrocytic α2 Na,K ATPase. Investigating the mechanisms underlying the facilitation of cortical spreading depression (CSD) in a genetic mouse model of FHM2 uncovers insights into migraine pathophysiology.

The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity–dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.

Removal of synaptically-released glutamate by astrocytes is necessary to spatially and temporally limit neuronal activation. Recent evidence suggests that astrocytes may have specialized functions in specific circuits, but the extent and significance of such specialization are unclear. By performing direct patch-clamp recordings and two-photon glutamate imaging, we report that in the somatosensory cortex, glutamate uptake by astrocytes is slower during sustained synaptic stimulation when compared to lower stimulation frequencies. Conversely, glutamate uptake capacity is increased in the frontal cortex during higher frequency synaptic stimulation, thereby limiting extracellular buildup of glutamate and NMDA receptor activation in layer 5 pyramidal neurons. This efficient glutamate clearance relies on Na + /K + -ATPase function and both GLT-1 and non-GLT-1 transporters. Thus, by enhancing their glutamate uptake capacity, astrocytes in the frontal cortex may prevent excessive neuronal excitation during intense synaptic activity. These results may explain why diseases associated with network hyperexcitability differentially affect individual brain areas. Jennifer Romanos et al. investigate how differences in astrocyte-mediated glutamate clearance between the frontal and somatosensory cortex impact neuronal function. They find that the frontal cortex more efficiently clears glutamate when synaptic stimulation frequency is high and this may prevent excessive neuronal excitation during sustained synaptic activity.

Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

Astrocytes are crucial contributors to brain homeostasis. Yet the lack of ad hoc analysis tools has prevented in-depth characterization of astrocyte-derived signals. In a new study, the authors present an image-analysis toolbox that captures the complexity of astrocyte activity and enables our understanding of astrocytic physiology.

Memory formation is known to occur at the level of synaptic contacts between neurons. It therefore comes as a surprise that another type of brain cell, the astrocyte, is also involved in establishing memory. Role of astrocytes in learning and memory The role of astrocytes in synaptic plasticity has remained controversial. It has been suggested that astrocytes, the star-shaped glial cells found in the brain and spinal cord that were once considered merely passive support cells, are involved in inducing LTP (long-term potentiation) of synaptic transmission — a model for the mechanisms of memory — via the modulation of NMDA-receptor activation and postsynaptic Ca 2+ entry. A new study provides more support for that theory by demonstrating that the inhibition of d-serine release from individual astrocytes blocks the potentiation of many nearby neuronal junctions.