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SARS-CoV-2, which causes the Coronavirus Disease 2019 (COVID-19) pandemic, has a brain neurotropism through binding to the receptor angiotensin-converting enzyme 2 expressed by neurones and glial cells, including astrocytes and microglia. Systemic infection which accompanies severe cases of COVID-19 also triggers substantial increase in circulating levels of chemokines and interleukins that compromise the blood-brain barrier, enter the brain parenchyma and affect its defensive systems, astrocytes and microglia. Brain areas devoid of a blood-brain barrier such as the circumventricular organs are particularly vulnerable to circulating inflammatory mediators. The performance of astrocytes and microglia, as well as of immune cells required for brain health, is considered critical in defining the neurological damage and neurological outcome of COVID-19. In this review, we discuss the neurotropism of SARS-CoV-2, the implication of neuroinflammation, adaptive and innate immunity, autoimmunity, as well as astrocytic and microglial immune and homeostatic functions in the neurological and psychiatric aspects of COVID-19. The consequences of SARS-CoV-2 infection during ageing, in the presence of systemic comorbidities, and for the exposed pregnant mother and foetus are also covered.

ATP receptor mediated Ca2+ signaling was recorded from Bergmann glial cells in cerebellar slices obtained from mice of different ages (postnatal days 6 to 45). To measure the cytoplasmic concentration of Ca2+ ([Ca2+]in), either individual cells were loaded with the Ca(2+)-sensitive probes using the whole cell patch clamp technique or slices were incubated with the dye and the microfluorimetric system was focused on individual cells. Signals were recorded either with single-detector microfluorimetry of the dye fura-2 or by confocal laser scanning microfluorimetry (fluo-3-based recordings). Extracellular application of 100 microns ATP caused a transient elevation of [Ca2+]in, which amplitude was significantly higher in Bergmann glial cell processes as compared with their soma. The rank order of potency for the purinoreceptor agonists was: ADP > or = ATP > UTP >> AMP = adenosine = alpha, beta-methylene-ATP. ATP-triggered Ca2+ transients were reversibly inhibited by the P2 purinoreceptor agonist suramin (100 microM). The involvement of P2 metabotropic receptors is inferred by the observation that ATP mediated cytoplasmic Ca2+ transients were not associated with a measurable change in membrane conductance. The [Ca2+]in increase was due to release from inositol-1,4,5-trisphosphate (InsP3)-sensitive intracellular stores since responses were still observed in Ca(2+)-free extracellular solutions and were irreversibly blocked by the inhibitor of the sarco(endo)plasmic reticulum Ca2+ ATPase, thapsigargin, and by the competitive inhibitor of the InsP3-gated intracellular Ca2+ channels heparin. Intracellular dialysis altered the refilling process of the InsP3-sensitive stores, suggesting that cytoplasmic factors control ATP mediated Ca2+ signalling.

The endoplasmic reticulum (ER) is a universal signalling organelle, which regulates a wide range of neuronal functional responses. Calcium release from the ER underlies various forms of intracellular Ca 2+ signalling by either amplifying Ca 2+ entry through voltage-gated Ca 2+ channels by Ca 2+ -induced Ca 2+ release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca 2+ release (IICR). The ER Ca 2+ store emerges as a single interconnected pool, thus allowing for a long-range Ca 2+ signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca 2+ concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca 2+ homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca 2+ handling may be involved in pathogenesis of various neurodegenerative diseases including brain ischemia and Alzheimer dementia.

We define a new concept of 'active milieu' that unifies all components of nervous tissue (neuronal and glial compartments, extracellular space, extracellular matrix, and vasculature) into a dynamic information processing system. Within this framework, we focus on the role of astrocytic processes, classified into organellecontaining branches and organelle-free leaflets. We argue that astrocytic branches with emanating leaflets are homologous to dendritic shafts with spines. Within the active milieu, astrocytic processes are engaged in reciprocal interactions with neuronal compartments and communication with other cellular and non-cellular elements of the nervous tissue. The concept of the active milieuAxons of neurons provide the input and output of the central nervous system, whereas the intricate web of neurons, glia, and vasculature underlies information processing and defines the central nervous system function as an organ. The concept of tripartite synapse [1] has been instrumental in rethinking the role of astrocytes in synaptic transmission. Subsequent morphological analyses identified additional components of the synaptic structure. These components include microglial processes and the extracellular matrix (ECM), thus upgrading the tripartite paradigm to tetra-or pentapartite synapse [2,3]. These convolutions reflect a high degree of complexity of the perisynaptic microenvironment, a subject of remarkable morphological plasticity. In particular, interactions of synapses with their microenvironment are influenced by the interposition of individual synapses and nearby compartments of non-neuronal cells and extracellular space (ECS). Here we argue that the expanding knowledge on physiological interactions of cellular and non-cellular components of nervous tissue necessitates advancing the concept of 'tri-(multi)-partite synapse' to a concept we name 'active milieu'. The active milieu is based on the dynamic interposition and interaction among compartments of neurons, astrocytes, oligodendrocytes, microglia, blood vessels, ECS, and ECM (Box 1 and Figure 1). In the framework of this concept, neuronal activity not only propagates from one neuron to another but also signals to other cellular and noncellular elements, which respond to this signal and affect all components of nervous tissue.

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Calcium signalling system controls majority of cellular reactions. Calcium signals occurring within tightly regulated temporal and spatial domains, govern a host of Ca 2+dependent enzymes, which in turn determine specified cellular responses. Generation of Ca 2+ signals is achieved through coordinated activity of several families of Ca 2+ channels and transporters differentially distributed between intracellular compartments. Cell damage induced by environmental insults or by overstimulation of physiological pathways results in pathological Ca 2+ signals, which trigger necrotic or apoptotic cellular death

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