Calcium signaling in astrocytes and gliotransmitter release

Abstract

Glia are as numerous in the brain as neurons and widely known to serve supportive roles such as structural scaffolding, extracellular ionic and neurotransmitter homeostasis, and metabolic support. However, over the past two decades, several lines of evidence indicate that astrocytes, which are a type of glia, play active roles in neural information processing. Astrocytes, although not electrically active, can exhibit a form of excitability by dynamic changes in intracellular calcium levels. They sense synaptic activity and release neuroactive substances, named gliotransmitters, that modulate neuronal activity and synaptic transmission in several brain areas, thus impacting animal behavior. This "dialogue" between astrocytes and neurons is embodied in the concept of the tripartite synapse that includes astrocytes as integral elements of synaptic function. Here, we review the recent work and discuss how astrocytes via calcium-mediated excitability modulate synaptic information processing at various spatial and time scales.

Keywords: astrocyte; calcium signaling; gliotransmission; plasticity; tripartite synapse.

FIGURE 1

Synaptic regulation of astrocyte Ca²⁺ signaling. Astrocyte leaflets sense and respond to synaptic activity through neurotransmitter receptors and transmitter transporters. Ca²⁺ transients are triggered by Ca²⁺ entry and by Ca²⁺ release from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptors (IP3R) after G-protein-coupled receptor (GPCR) activation. Mitochondria also participate in Ca²⁺ loci by action of mitochondrial permeability transition pore (mPTP) and mitochondria sodium/calcium exchanger (NCX). Ca²⁺ can be removed from the cell by action of Ca²⁺ ATPase (PCMA) or mobilized to the ER by sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). NKA, Na+/K+ ATPase; InsP₃, inositol 1,4,5-trisphosphate; MCU, mitochondria Ca²⁺ uniporter; ROS, reactive oxygen species.

FIGURE 2

Schematic of Ca²⁺ dependent and independent gliotransmitter release. Astrocytes can release gliotransmitters through a variety of mechanisms dependent and independent of calcium. Glutamate has been shown to be released via a variety of mechanisms. These mechanisms include exocytosis, lysosomes, hemichannels, exchangers, anion channels, antiporters as well as channels such as TREK-1 and Bestropin-1 (BEST-1) (Araque et al., 2000; Montana et al., 2004; Zhang et al., 2004; Xu et al., 2007; Malarkey and Parpura, 2008; Yang et al., 2019; Okada et al., 2021). GABA on the other hand, has been shown to be released via BEST-1, hemichannels, as well as anion channels and transporters (Kozlov et al., 2006; Jiménez-González et al., 2011; Le Meur et al., 2012; Yoon and Lee, 2014; Christensen et al., 2018; Kwak et al., 2020). ATP can be released via hemichannels, exocytosis, anion channels, and lysosomes (Bezzi and Volterra, 2001; Fujii et al., 2017; Xiong et al., 2018). Lastly, D-serine has been shown to be released via exocytosis, BEST-1, and hemichannels (Wolosker et al., 1999; Martineau et al., 2013; Sild and Van Horn, 2013; Herman, 2018; Koh et al., 2022; Linsambarth et al., 2022; Park et al., 2022; Tapanes et al., 2022). Created with BioRender.com.