Gliotransmitter Release from Astrocytes: Functional, Developmental, and Pathological Implications in the Brain

Abstract

Astrocytes comprise a large population of cells in the brain and are important partners to neighboring neurons, vascular cells, and other glial cells. Astrocytes not only form a scaffold for other cells, but also extend foot processes around the capillaries to maintain the blood-brain barrier. Thus, environmental chemicals that exist in the blood stream could have potentially harmful effects on the physiological function of astrocytes. Although astrocytes are not electrically excitable, they have been shown to function as active participants in the development of neural circuits and synaptic activity. Astrocytes respond to neurotransmitters and contribute to synaptic information processing by releasing chemical transmitters called "gliotransmitters." State-of-the-art optical imaging techniques enable us to clarify how neurotransmitters elicit the release of various gliotransmitters, including glutamate, D-serine, and ATP. Moreover, recent studies have demonstrated that the disruption of gliotransmission results in neuronal dysfunction and abnormal behaviors in animal models. In this review, we focus on the latest technical approaches to clarify the molecular mechanisms of gliotransmitter exocytosis, and discuss the possibility that exposure to environmental chemicals could alter gliotransmission and cause neurodevelopmental disorders.

Keywords: astrocytes; exocytosis; glial cell; gliotransmitter; neurodevelopmental disorders; optical imaging; synaptic activity.

Figure 1

Astrocytes have close morphological and functional associations with microvasculature and neurons. (A) Location of astrocytes around blood vessels and neurons in the central nervous system. Note that single astrocytes make contact with a large number of blood vessels and neurons through their numerous processes. (B) Schematic diagram showing the blood–brain barrier and its functions in selecting and transporting various molecules from the blood stream. Although, vascular endothelial cells form robust tight junctions that prevent infiltration of most soluble molecules, hydrophobic lipids can penetrate across the plasma membrane. In addition, certain soluble molecules such as glucose are actively transported across the endothelial cells via their specific transporters, and some peptides are taken up by selective vesicular transcytosis. (C) Schematic diagram showing the tripartite synapse and complex signaling interactions mediated by neurotransmitters and gliotransmitters. Neurotransmitters released from presynaptic terminals such as glutamate act not only on postsynapses but also on astrocytes. Activated astrocytes release gliotransmitters including glutamate, D-serine, and ATP, via vesicular exocytosis (and also possibly via hemichannels for ATP). Released gliotransmitters bind to presynaptic and postsynaptic receptors to regulate synaptic transmission. Astrocytes also take part in clearance of extracellular glutamate via glutamate transporters.

Figure 2

Precise intracellular machinery involved in the release of glutamate, D-serine, and ATP from astrocytes. Glutamate and D-serine are taken up into synaptic-like vesicles through (1) VGLUT and (2) vesicular D-serine transporters (VSERT), respectively. These synaptic-like vesicles fuse to the plasma membrane, mediated by SNARE proteins including VAMP2 or VAMP3, in response to [Ca²⁺]_i increase. In contrast, ATP is released through secretory lysosomes. Storage of ATP into secretory lysosomes is achieved by (3) VNUT. Through the interaction of SNARE proteins including TI-VAMP, ATP-containing secretory lysosomes are Ca²⁺-dependently exocytosed. Moreover, the existence of other release mechanisms has been discovered: (4) reverse operation of plasma membrane glutamate transporters, (5) cell swelling-induced anion transporter (VRAC) opening, (6) release via P2X₇ receptors, and (7) gap junction channels (hemichannels) on the cell surface of astrocytes.