Elsevier

Neuroscience

Volume 323, 26 May 2016, Pages 67-75
Neuroscience

Astrocytic vesicles and gliotransmitters: Slowness of vesicular release and synaptobrevin2-laden vesicle nanoarchitecture

https://doi.org/10.1016/j.neuroscience.2015.02.033Get rights and content

Highlights

  • Unlike neurons, astrocytic vesicles have one third of synaptobrevin 2 (Sb2) molecules in a vesicle.

  • The paucity of Sb2 in astrocytes may determine the slow secretory profile.

  • Distinct mobility of glutamatergic vs. peptidergic vesicles contributes to astrocytic plasticity.

Abstract

Neurotransmitters released at synapses activate neighboring astrocytes, which in turn, modulate neuronal activity by the release of diverse neuroactive substances that include classical neurotransmitters such as glutamate, GABA or ATP. Neuroactive substances are released from astrocytes through several distinct molecular mechanisms, for example, by diffusion through membrane channels, by translocation via plasmalemmal transporters or by vesicular exocytosis. Vesicular release regulated by a stimulus-mediated increase in cytosolic calcium involves soluble N-ethyl maleimide-sensitive fusion protein attachment protein receptor (SNARE)-dependent merger of the vesicle membrane with the plasmalemma. Up to 25 molecules of synaptobrevin 2 (Sb2), a SNARE complex protein, reside at a single astroglial vesicle; an individual neuronal, i.e. synaptic, vesicle contains ∼70 Sb2 molecules. It is proposed that this paucity of Sb2 molecules in astrocytic vesicles may determine the slow secretion. In the present essay we shall overview multiple aspects of vesicular architecture and types of vesicles based on their cargo and dynamics in astroglial cells.

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).

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