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.

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

“…For example, astrocytes control neuronal excitability by controlling levels of extracellular neurotransmitters (including GABA) (Liu et al, 2022) and extracellular K + levels. Moreover, these cells also play essential roles in (inhibitory) synapses formation and maintenance (Takano et al, 2020;Baldwin et al, 2021;Lee et al, 2021;Wahis et al, 2021b) and can modulate synaptic activity through the release of numerous gliotransmitters (Durkee and Araque, 2019;Goenaga et al, 2023). Since α1-NAR signaling in astrocytes seems to affect some, if not all, of these mechanisms (Wahis and Holt, 2021), it would be interesting to investigate if any of their associated molecular pathways are altered following astrocyte-specific KO of Adra1a, for instance by using a single cell omics approach and look for differential expression of key genes and/or proteins.…”

“…However, changes in their local environment, principally neuronal activity and the resulting release of neurotransmitters and/or neuromodulators, elicits transient fluctuations in their intracellular calcium ([Ca 2+ ]). These [Ca 2+ ] transients are thought to regulate astrocyte functions, including the release of gliotransmitters, which reciprocally regulate the activity of neural circuits (Rusakov, 2015;Goenaga et al, 2023). These key functions have been confirmed in numerous studies, using a variety of animal models, underlying the importance of astrocytes for correct neural circuit function and the generation of specific behaviors (Nagai et al, 2021).…”

Astrocytes in fragile X syndrome

“…Astrocytes exhibit intracellular Ca 2+ currents which can modulate synapse function by altering gliotransmitter release ( Goenaga et al, 2023 ). There is ample evidence that these Ca 2+ signals are altered in the context of FMRP-deficient astrocytes.…”

“…A crucial function of astrocytes is to provide metabolic support to neurons ( Turner and Adamson, 2011 ). They display dynamic activity in the form of intracellular calcium levels, which control the release of neuroactive gliotransmitters ( Goenaga et al, 2023 ). Astrocytes induce the development and destruction of both excitatory and inhibitory synapses and contribute to short- and long-term brain plasticity through distinct mechanisms ( Perez-Catalan et al, 2021 ).…”

Non-neoplastic astrocytes: key players for brain tumor progression

“…Being part of the “tripartite” synapse ( Araque et al, 1999 ), astrocytes respond to neurotransmitter release by presynaptic terminals with an increase in intracellular Ca 2+ , and consequent release of “gliotransmitters” that can act regulating synaptic plasticity at local synapse ( Fellin et al, 2006 ; Di Castro et al, 2011 ). Moreover, intracellular calcium increase can be spread to other connected astrocytes ( Bazargani and Attwell, 2016 ; Goenaga et al, 2023 ) resulting in neurotransmitter release and modulation of synapses at the level of network activity ( Fellin, 2009 ; Miguel-Quesada et al, 2023 ).…”