The glial cells astrocytes have long been recognized as important neuron-supporting elements in brain development, homeostasis, and metabolism. After the discovery that the reciprocal communication between astrocytes and neurons is a fundamental mechanism in the modulation of neuronal synaptic communication, over the last two decades astrocytes became a hot topic in neuroscience research. Crucial to their functional interactions with neurons are the cytosolic Ca²⁺ elevations that mediate gliotransmission. Large attention has been posed to the so-called Ca²⁺microdomains, dynamic Ca²⁺ changes spatially restricted to fine astrocytic processes including perisynaptic astrocytic processes (PAPs). With presynaptic terminals and postsynaptic neuronal membranes, PAPs compose the tripartite synapse. The distinct spatial-temporal features and functional roles of astrocyte microdomain Ca²⁺ activity remain poorly defined. However, thanks to the development of genetically encoded Ca²⁺ indicators (GECIs), advanced microscopy techniques, and innovative analytical approaches, Ca²⁺ transients in astrocyte microdomains were recently studied in unprecedented detail. These events have been observed to occur much more frequently (∼50–100-fold) and dynamically than somatic Ca²⁺ elevations with mechanisms that likely involve both IP₃-dependent and -independent pathways. Further progress aimed to clarify the complex, dynamic machinery responsible for astrocytic Ca²⁺ activity at microdomains is a crucial step in our understanding of the astrocyte role in brain function and may also reveal astrocytes as novel therapeutic targets for different brain diseases. Here, we review the most recent studies that improve our mechanistic understanding of the essential features of astrocyte Ca²⁺ microdomains.

At glutamatergic synapses, astrocytes respond to the neurotransmitter glutamate with intracellular Ca²⁺ elevations and the release of gliotransmitters that modulate synaptic transmission. While the functional interactions between neurons and astrocytes have been intensively studied at glutamatergic synapses, the role of astrocytes at GABAergic synapses has been less investigated. In the present study, we combine optogenetics with 2-photon Ca²⁺ imaging experiments and patch-clamp recording techniques to investigate the signaling between Somatostatin (SST)-releasing GABAergic interneurons and astrocytes in brain slice preparations from the visual cortex (VCx). We found that an intense stimulation of SST interneurons evokes Ca²⁺ elevations in astrocytes that fundamentally depend on GABA_B receptor (GABA_BR) activation, and that this astrocyte response is modulated by the neuropeptide somatostatin. After episodes of SST interneuron hyperactivity, we also observed a long-lasting reduction of the inhibitory postsynaptic current (IPSC) amplitude onto pyramidal neurons (PNs). This reduction of inhibitory tone (i.e., disinhibition) is counterbalanced by the activation of astrocytes that upregulate SST interneuron-evoked IPSC amplitude by releasing ATP that, after conversion to adenosine, activates A₁Rs. Our results describe a hitherto unidentified modulatory mechanism of inhibitory transmission to VCx layer II/III PNs that involves the functional recruitment of astrocytes by SST interneuron signaling.

Astrocytes from different brain regions respond with Ca²⁺ elevations to the catecholamine norepinephrine (NE). However, whether this noradrenergic-mediated signaling is present in astrocytes from the ventral tegmental area (VTA), a dopaminergic circuit receiving noradrenergic inputs, has not yet been investigated. To fill in this gap, we applied a pharmacological approach along with two-photon microscopy and an AAV strategy to express a genetically encoded calcium indicator in VTA astrocytes. We found that VTA astrocytes from both female and male young adult mice showed a strong Ca²⁺ response to NE at both soma and processes. Our results revealed that Gq-coupled α1 adrenergic receptors, which elicit the production of IP3, are the main mediators of the astrocyte response. In mice lacking the IP3 receptor type-2 (IP3R2^−/− mice), we found that the astrocyte response to NE, even if reduced, is still present. We also found that in IP3R2^−/− astrocytes, the residual Ca²⁺ elevations elicited by NE depend on the release of Ca²⁺ from the endoplasmic reticulum, through IP3Rs different from IP3R2. In conclusion, our results reveal VTA astrocytes as novel targets of the noradrenergic signaling, opening to new interpretations of the cellular and molecular mechanisms that mediate the NE effects in the VTA.

Chronic pain is a debilitating, life-altering condition that affects a significant portion of the global population, impacting approximately one fifth of people in Europe and one third of people worldwide. Clinical and experimental efforts are increasingly converging to deepen our comprehension of the molecular, cellular and circuit-level mechanisms underlying persistent pain. While most studies have traditionally focused on alterations of nociceptive pathways in neurons, growing evidence highlights the critical role of astrocytes in modulating these pathways and contributing to the development of the central sensitization that characterizes chronic pain. Moreover, astrocytes are also implicated in pain-associated maladaptive behaviours and cognitive impairments. In this context, we review the latest findings on astrocyte involvement in chronic pain and its related mood and cognitive comorbidities. Graphical Abstract

Anxiety is a physiological, emotional response that anticipates distal threats. When kept under control, anxiety is a beneficial response, helping animals to maintain heightened attention in environments with potential dangers. However, an overestimation of potential threats can lead to an excessive expression of anxiety that, in humans, may evolve into anxiety disorders. Pharmacological treatments show variable efficacy among patients, highlighting the need for more efforts to better understand the pathogenesis of anxiety disorders. Mounting evidence suggests that astrocytes, a type of glial cells, are active partners of neurons in brain circuits and in the regulation of behaviors under both physiological and pathological conditions. In this review, I summarize the current literature on the role of astrocytes from different brain regions in modulating anxious states, with the goal of exploring novel cerebral mechanisms to identify potential innovative therapeutic targets for the treatment of anxiety disorders.