Astroglial cells, due to their passive electrical properties, were long considered subservient to neurons and to merely provide the framework and metabolic support of the brain. Although astrocytes do play such structural and housekeeping roles in the brain, these glial cells also contribute to the brain's computational power and behavioural output. These more active functions are endowed by the Ca2+-based excitability displayed by astrocytes. An increase in cytosolic Ca2+ levels in astrocytes can lead to the release of signalling molecules, a process termed gliotransmission, via the process of regulated exocytosis. Dynamic components of astrocytic exocytosis include the vesicular-plasma membrane secretory machinery, as well as the vesicular traffic, which is governed not only by general cytoskeletal elements but also by astrocyte-specific IFs (intermediate filaments). Gliotransmitters released into the ECS (extracellular space) can exert their actions on neighbouring neurons, to modulate synaptic transmission and plasticity, and to affect behaviour by modulating the sleep homoeostat. Besides these novel physiological roles, astrocytic Ca2+ dynamics, Ca2+-dependent gliotransmission and astrocyte–neuron signalling have been also implicated in brain disorders, such as epilepsy. The aim of this review is to highlight the newer findings concerning Ca2+ signalling in astrocytes and exocytotic gliotransmission. For this we report on Ca2+ sources and sinks that are necessary and sufficient for regulating the exocytotic release of gliotransmitters and discuss secretory machinery, secretory vesicles and vesicle mobility regulation. Finally, we consider the exocytotic gliotransmission in the modulation of synaptic transmission and plasticity, as well as the astrocytic contribution to sleep behaviour and epilepsy.
astrocyte; exocytosis; epilepsy; sleep; synaptic transmission; traffic; ADA, adenosine deaminase; ADK, adenosine kinase; ANP, atrial natriuretic peptide; 2-APB, diphenylboric acid 2-aminoethyl ester; [Ca2+]i, cytosolic/intracellular Ca2+ levels; Cm, membrane capacitance; dnSNARE, dominant negative SNARE; ECS, extracellular space; EGFP, enhanced GFP; Emd, emerald green; ENT, equilibrative nucleoside transporter; ER, endoplasmic reticulum; GABA, γ-aminobutyric acid; GAT-1, GABA transporter-1; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; GluR, glutamate receptor; HEK-293 cells, human embryonic kidney cells; IF, intermediate filament; InsP3R, inositol 1,4,5-trisphosphate receptor; LTP, long-term potentiation; mGluR, metabotropic GluR; NCX, Na+/Ca2+ exchanger; NMDAR, N-methyl-d-aspartate receptor; Ru360, Ruthenium 360; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; SNARE, soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor; SOCE, store-operated Ca2+ entry; Sb2, synaptobrevin 2; SNAP-23, 23 kDa synaptosome-associated protein; SWA, slow wave activity; TIRFM, total internal reflection microscopy; TRP, transient receptor potential; TRPC1, TRP canonical 1; V-ATPase, vacuolar type of proton ATPase; VGCC, voltage-gated Ca2+ channels; VGLUT, vesicular glutamate transporter
Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron–glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron–glia networks.
astrocytes; intracellular Ca2+; gliotransmitter release; neuron–glia communication