Astroglial Excitability and Gliotransmission: An Appraisal of Ca²⁺ as a Signalling Route

Abstract

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.

Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus

“…The astrocytic Ca 2þ responses were largely mediated by metabotropic glutamate receptor type 5, but ionotropic receptors were also involved [45]. Thalamic astrocytes have been shown to release glutamate which triggers slow NMDA currents in neighbouring neurons [46], but whether this release occurs through Ca 2þ -dependent exocytosis [47] still remains to be demonstrated. On the other hand, the influx of Na þ through AMPA receptors and its spread through gap junctions to neighbouring astrocytes might enhance the activity of Na þ /K þ ATPase, stimulate glycolysis and increase [Ca 2þ ] i by activation of Na þ /Ca 2þ exchangers [48][49][50] [53,54].…”

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

“…61 The most important role played by NCX1 in astrocytes is related to the regulation of gliotransmitter release. 18 Hence, mild depolarization of astrocytes forces NCX to operate in the reverse mode and generates cytosolic Ca 2 þ increases leading to release of gliotransmitters, such as glutamate. 62,63 Only few studies have investigated the pathophysiological role of astrocytic NCX in ischemic astrocytes.…”

Astrocytes in endocannabinoid signalling

“…Indeed, astrocytes respond with intracellular calcium elevations to neurotransmitters released from synaptic terminals [14 -18]. These calcium elevations have been shown to stimulate the release of gliotransmitters through different mechanisms [19][20][21][22][23][24], which still remain debated (for recent reviews, see [25][26][27]). …”