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.

Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels

“…By contrast, it is well established that astrocytes are capable of releasing transmitters like glutamate, aspartate, D-serine, taurine and ATP (Harada et al, 2015;Kimelberg et al, 1990;Parpura et al, 1994;Pasantes-Morales et al, 1994). It has been suggested that this 'gliotransmitter' release influences neuronal excitability, adding a novel component to neuronal information processing (Verkhratsky et al, 2016(Verkhratsky et al, , 2012.…”

“…Neurons and astrocytes can release neurotransmitters and other signaling molecules not only by vesicular exocytosis, but also through channel-like mechanisms (Hamilton and Attwell, 2010;Harada et al, 2015;Kimelberg et al, 1990;Pasantes-Morales et al, 1994;Verkhratsky et al, 2016Verkhratsky et al, , 2012. Several channels have been implicated in channel-like neurotransmitter release, including connexin hemichannels and pannexins (Montero and Orellana, 2015;Orellana and Stehberg, 2014), P2X7 receptors (Duan et al, 2003), bestrophins (Lee et al, 2010), and the volume-regulated anion channel (VRAC) (Kimelberg et al, 1990;Pasantes-Morales et al, 1994).…”

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…VDAC1 downregulation has been reported to reduce cellular ATP levels and induce mitochondrial fragmentation (45,46), eventually leading to by guest, on May 11, 2018 www.jlr.org Downloaded from neurodegeneration. In astrocytes, VDAC1 is critical for secretion of ATP, a gliotransmitter regulating synaptic plasticity and neuronal function (47)(48)(49)(50). Most recently, VDAC1 closure by tubulin has been suggested to be critical for the Warburg effect, a metabolic switch from mitochondria-mediated oxidative phosphorylation to glycolysis for ATP production, often observed in cancer cells (51)(52)(53).…”

Astrocyte-Synapse Receptor Coupling in Tripartite Synapses: A Mechanism for Self-Observing Robots

“…The main receptors activated by GLU are kainate receptors, metabotrophic GLU receptors, and N-methyl-D-asparate (NMDA) receptors [37]. Several release mechanisms play a role in gliotransmission [40]. There are reverse operations of glutamate transporters on the plasma membrane; opening of anion transporters induced by cell-swelling; purine 2 × 7 receptors release GLU; gap junction hemichannels on the astrocytic cell membrane also release GLU.…”