Astrocytic vesicles and gliotransmitters: Slowness of vesicular release and synaptobrevin2-laden vesicle nanoarchitecture
Introduction
The concept of neuroglia as the connective tissue of the central nervous system (CNS) was introduced in the middle of the 19th century by Rudolf Virchow (Virchow, 1858, Kettenmann and Verkhratsky, 2008). Numerous hypotheses of the neuroglial function were developed by the beginning of the 20th century (Schleich, 1894, Ramón y Cajal, 1895, Golgi, 1903, Lugaro, 1907), which envisaged the role of these cells in modulating synaptic transmission, supporting brain metabolism, controlling blood flow and regulating sleep behavior.
In 1910 Jean Nageotte suggested, based on his microscopic observations, that glial cells (astroglia in particular) act as secretory elements of the CNS (Nageotte, 1910). This hypothesis had been experimentally confirmed in the last quarter of the 20th century, when it was discovered that not only neurons, but also astrocytes, release chemical transmitters (generally known as gliotransmitters, merely to indicate the cellular source of these compounds), which signal to the neighboring cells (this signaling being termed “gliotransmission”). The concept of gliotransmission emerged after the discovery that cultured astrocytes responded to the neurotransmitters, such as glutamate, by generating cytosolic calcium signals (Cornell-Bell et al., 1990) and thereby exhibiting an ability to “sense” glutamatergic synaptic transmission (Dani et al., 1992). This was followed by the discovery that astrocytic calcium dynamics can trigger astrocyte-neuron signaling, with at least two underlying mechanisms: direct, perhaps using gap junctions (Nedergaard, 1994), and indirect utilizing glutamate released from astrocytes via Ca2+-dependent regulated exocytosis (Parpura, 1994). The later mechanism led to the discovery of gliotransmission-based modulation of synaptic transmission (Araque et al., 1998). These results, and many that followed, established the concept that a synapse consists of at least three elements, first termed the “synaptic triad” (Kettenmann et al., 1996), and later the “tripartite synapse“ (Araque et al., 1999). Thus, in addition to the classical pre- and post-synaptic elements, astrocytes provide the third synaptic element that contributes an additional functional level of complexity in synaptic physiology. This concept has evolved further into the multi-partite synapse which in addition includes the extracellular matrix and microglial processes (Dityatev and Rusakov, 2011, Verkhratsky and Nedergaard, 2014). Since astrocytes can detect synaptic activity and signal back to neuronal networks with the release of chemical transmitters mainly using the vesicular exocytosis as an underlying mechanism governing this secretion, in this review we overview some aspects of vesicular architecture and dynamics of these organelles in astroglial cells.
Section snippets
Mechanisms of gliotransmitter release from astrocytes: eminence of regulated exocytosis
Several mechanisms of gliotransmitter release appear to coexist in a single astrocyte (Parpura and Zorec, 2010, Parpura and Verkhratsky, 2012). In addition to (i) the vesicle-based mechanisms, astroglial cells can release chemical messengers through: (ii) plasmalemmal channels like, for example, opening of anion channels, induced by cell swelling (Pasantes Morales and Schousboe, 1988, Kimelberg et al., 1990) or by an increase in cytosolic calcium (Woo et al., 2012); through (iii) unpaired
Regulated exocytosis in astrocytes is slow
The properties of vesicle-based mechanisms of gliotransmission can be studied at the cellular level by monitoring changes in the plasma membrane area, since the fusion of the vesicle with the plasmalemma contributes to changes in the surface membrane area. This can be monitored by measuring membrane capacitance (Cm), which is linearly related to the membrane area (Neher and Marty, 1982). This technique was used in cultured astrocytes (Kreft et al., 2004), to test the hypothesis that an increase
Amino acids as astrocytic transmitters
In astrocytes, glutamate can be synthesized de novo (Hertz et al., 1999), as a by-product of the tricarboxylic acid (TCA) cycle and involving the astrocyte-specific enzyme pyruvate carboxylase. Glutamate is converted from the TCA cycle intermediate, α-ketoglutarate, usually via transamination of aspartate by aspartate aminotransferase (Westergaard et al., 1996). In addition, glutamate may enter the cytoplasm via the plasma membrane transporters. Once in the cytosol, glutamate is then
Dynamics of secretory vesicles in astrocytes
Secretory organelles storing transmitters in astrocytes are morphologically heterogeneous, consisting of small synaptic-like vesicles, endolysosomes, peptidergic, recycling and other vesicles (Guček et al., 2012). At the ultrastructural level, they can appear electron-lucent or exhibit a dense or a less-dense core (Parpura and Zorec, 2010, Bergersen et al., 2011). An essential property of these secretory organelles is that they contain SNARE proteins that mediate the exocytotic process (Parpura
Conclusions
In the present essay we overviewed the exocytotic release of neuroactive substances form astrocytes with an emphasis on the vesicular architecture and traffic. Experimental evidence has revealed that secretory vesicles, compulsory morphological elements of exocytosis, are present in astrocytes, as reviewed (Montana et al., 2006, Parpura and Zorec, 2010, Guček et al., 2012). In astrocytes, Sb2 can be associated with vesicular structures. When compared to neurons, astrocytic vesicles have thrifty
Acknowledgments
VP is supported by the National Institutes of Health (The Eunice Kennedy Shriver National Institute of Child Health and Human Development award HD078678). RZ is supported by the grants P3 310, J3 4051, J3 3632, J36790 and J3 4146 from the Slovenian Research Agency (ARRS) and the EduGlia ITN EU grant. AV and JJR were supported by Alzheimer’s Research Trust (UK) Programme Grant (ART/PG2004A/1).
References (110)
- et al.
Tripartite synapses: glia, the unacknowledged partner
Trends Neurosci
(1999) - et al.
Immunogold detection of l-glutamate and d-serine in small synaptic-like microvesicles in adult hippocampal astrocytes
Cereb Cortex
(2011) - et al.
A regulated secretory pathway in cultured hippocampal astrocytes
J Biol Chem
(1999) Storage and release of ATP from astrocytes in culture
J Biol Chem
(2003)- et al.
Neuronal activity triggers calcium waves in hippocampal astrocyte networks
Neuron
(1992) - et al.
Molecular signals of plasticity at the tetrapartite synapse
Curr Opin Neurobiol
(2011) - et al.
P2Y1 receptor-evoked glutamate exocytosis from astrocytes - Control by tumor necrosis factor-alpha and prostaglandins
J Biol Chem
(2006) - et al.
Vesicular inhibitory amino acid transporter is expressed in gamma-aminobutyric acid (GABA)-containing astrocytes in rat pineal glands
Neurosci Lett
(2004) - et al.
Neuroglia: the 150 years after
Trends Neurosci
(2008) Introduction: regulated exocytosis
Cell Calcium
(2012)
Multiple calcium-dependent processes related to secretion in bovine chromaffin cells
Neuron
Vesicular nucleotide transporter is involved in ATP storage of secretory lysosomes in astrocytes
Biochem Biophys Res Commun
Exocytotic release of ATP from cultured astrocytes
J Biol Chem
The astrocyte excitability brief: from receptors to gliotransmission
Neurochem Int
Gliotransmission: exocytotic release from astrocytes
Brain Res Rev
Expression of synaptobrevin II, cellubrevin and syntaxin but not SNAP-25 in cultured astrocytes
FEBS Lett
Vesicle mobility studied in cultured astrocytes
Biochem Biophys Res Commun
Ca2+-dependent mobility of vesicles capturing anti-VGLUT1 antibodies
Exp Cell Res
Molecular anatomy of a trafficking organelle
Cell
Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate
NeuroReport
Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons
Eur J Neurosci
Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons
J Neurosci
Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons
J Neurosci
An energy budget for signaling in the grey matter of the brain
J Cereb Blood Flow Metab
Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes
Glia
Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate
Nat Neurosci
Calcium sensitivity of glutamate release in a calyx-type terminal
Science
Two forms of single vesicle astrocyte exocytosis imaged with total internal reflection fluorescence microscopy
Proc Natl Acad Sci USA
Purinergic signalling and the nervous system
Quantal components of the end-plate potential
J Physiol
“Kiss-and-run” glutamate secretion in cultured and freshly isolated rat hippocampal astrocytes
J Neurosci
Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling
Science
Connexins regulate calcium signaling by controlling ATP release
Proc Natl Acad Sci U S A
Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis
J Physiol
Protein hormone storage in secretory granules: mechanisms for concentration and sorting
Endocr Rev
P2X7 receptor-mediated release of excitatory amino acids from astrocytes
J Neurosci
The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate
Proc Natl Acad Sci USA
Opera omnia
Exocytosis in astrocytes: transmitter release and membrane signal regulation
Neurochem Res
Calcium dependence of the rate of exocytosis in a synaptic terminal
Nature
Long-term potentiation depends on release of d-serine from astrocytes
Nature
Astrocytes: glutamate producers for neurons
J Neurosci Res
C(a2+)-dependent glutamate release involves two classes of endoplasmic reticulum Ca(2+) stores in astrocytes
J Neurosci Res
Pannexin 1: the molecular substrate of astrocyte “hemichannels”
J Neurosci
SNAREs–engines for membrane fusion
Nat Rev Mol Cell Biol
Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes
Proc Natl Acad Sci USA
GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease
Nat Med
Neuron-derived d-serine release provides a novel means to activate N-methyl-d-aspartate receptors
J Biol Chem
Neuron-glia interactions in homeostasis and degeneration
Swelling-induced release of glutamate, aspartate and taurine from astrocyte cultures
J Neurosci
Cited by (46)
Purinergic signaling orchestrating neuron-glia communication
2020, Pharmacological ResearchAstrocytes in rapid ketamine antidepressant action
2020, NeuropharmacologyCitation Excerpt :During brain development, astrocytes (in the form of radial glia) generate neural progenitors and guide migrating neurones towards their destinations in the neocortex, and instruct them to form synapses that connect functional neuronal networks (Ullian et al., 2001). In the adult brain, astrocytes signal back to neurones by secreting gliosignalling molecules (Verkhratsky et al., 2016; Zorec et al., 2016) and other factors that regulate the strength of synapses essential for learning and memory formation (Clarke and Barres, 2013; Zorec et al., 2015). Astrocytes promote the survival of existing neurones (Seri et al., 2001).
Feedback adaptation of synaptic excitability via Glu:Na<sup>+</sup> symport driven astrocytic GABA and Gln release
2019, NeuropharmacologyCitation Excerpt :Importantly, these astrocytes have the potential to significantly modulate synaptic transmission (Barres, 2008; Gourine and Kasparov, 2011). Since circuit modulation via “vesicular gliotransmission” has been hypothesized [Agulhon et al., 2008; Araque et al., 2014; Volterra et al., 2014], it still generates some scepticism [Agulhon et al., 2008; Flanagan et al., 2018; Nedergaard and Verkhratsky, 2012; Sun et al., 2013; Zorec et al., 2016] or even refusal [Fujita et al., 2014]. In parallel, a non-canonical view of bidirectional neuron-astrocyte signalling has also emerged that places astrocytic [Na+] transients in the limelight [Brazhe et al., 2018; Breslin et al., 2018; Héja et al., 2009, 2012; Kirischuk et al., 2012; 2016; Langer et al., 2012; Rose and Chatton, 2016; Todd et al., 2017; Unichenko et al., 2012].
Astroglia-Derived ATP Modulates CNS Neuronal Circuits
2019, Trends in NeurosciencesCitation Excerpt :Arguments challenging the ‘gliotransmitter’ hypothesis were that (i) deleting IP3R2, that is responsible for Ca2+ release from the endoplasmic reticulum of astrocytes, had virtually no effect on synaptic transmission; (ii) in contrast to the cell body, Ca2+ stores are absent in small perisynaptic processes of astrocytes; and (iii) the expression of astrocytic mGlu5Rs, which were shown to stimulate the release of gliotransmitters, is undetectable after the third postnatal week in mice [46,48]. On the whole, arguments favoring [49,50] and refuting [51,52] the role of astrocytes in fast neurotransmission are roughly balanced. Nevertheless, it is an indisputable fact that the amount of glutamate released from healthy astrocytes is absolutely minuscule compared with its neuronal release.
The astrocyte biochemistry
2019, Seminars in Cell and Developmental BiologyCitation Excerpt :These cells are constantly collaborating with neurons and with each other to accurately accomplish functional tasks in the CNS [1,2,18–21]. Astrocytes are the most versatile cells in the CNS, having multiple layers of complexity and the ability to interact with neighboring cell types in the nervous tissue and to modulate their function [19,22,23]. Interestingly, the term astrocyte is derived from “astron”, a Greek word that means star, due to its characteristically stellar shape morphology [24].
Differential impairment of short working and spatial memories in a rat model of progressive Parkinson's disease onset: A focus on the prodromal stage
2019, Brain Research BulletinCitation Excerpt :Studies revealed, in the rat hippocampus, that an individual astrocyte can cover up to 140,000 synapses through the perisynaptic processes (Bushong et al., 2002). The close morphological apposition between neuron and astrocyte allows the latter to receive synaptic cleft signals and feedback by releasing their own signaling molecules such capacity has been sustained by the identification of vesicular release of gliosignal molecules named gliotransmitters (Zorec et al., 2016). Our study has revealed, in the hippocampus SLM region, a blunted and profound morphological astroglial changes with astrocyte multiplication leading to astrocytosis as well as increased processes length and decreased ramification level and astrocytic surface, while these changes were concomitant with a decline of short working memory performance in the reserpine rats during 13 days treatment.