The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition

Abstract

Astroglial networks constitute a non-neuronal communication system in the brain and are acknowledged modulators of synaptic plasticity. A sophisticated set of transmitter receptors in combination with distinct secretion mechanisms enables astrocytes to sense and modulate synaptic transmission. This integrative function evolved around intracellular Ca2+ signals, by and large considered as the main indicator of astrocyte activity. Regular brain physiology meticulously relies on the constant reciprocity of excitation and inhibition (E/I). Astrocytes are metabolically, physically, and functionally associated to the E/I convergence. Metabolically, astrocytes provide glutamine, the precursor of both major neurotransmitters governing E/I in the central nervous system (CNS): glutamate and γ-aminobutyric acid (GABA). Perisynaptic astroglial processes are structurally and functionally associated with the respective circuits throughout the CNS. Astonishingly, in astrocytes, glutamatergic as well as GABAergic inputs elicit similar rises in intracellular Ca2+ that in turn can trigger the release of glutamate and GABA as well. Paradoxically, as gliotransmitters, these two molecules can thus strengthen, weaken or even reverse the input signal. Therefore, the net impact on neuronal network function is often convoluted and cannot be simply predicted by the nature of the stimulus itself. In this review, we highlight the ambiguity of astrocytes on discriminating and affecting synaptic activity in physiological and pathological state. Indeed, aberrant astroglial Ca2+ signaling is a key aspect of pathological conditions exhibiting compromised network excitability, such as epilepsy. Here, we gather recent evidence on the complexity of astroglial Ca2+ signals in health and disease, challenging the traditional, neuro-centric concept of segregating E/I, in favor of a non-binary, mutually dependent perspective on glutamatergic and GABAergic transmission.

Calcium Signals in Astrocyte Microdomains, a Decade of Great Advances

“…The release of Ca 2+ from the endoplasmic reticulum (ER) into the cytosol can be initiated by stimulation of metabotropic G q G-protein-coupled receptors (GPCRs) through activation of PLC, production of IP 3 , and activation of IP 3 receptors (IP 3 Rs) on ER membranes ( Perea et al, 2009 ). Notably, G i coupled GPCRs, such as GABA B receptors, can induce Ca 2+ transients in astrocytes through an intracellular pathway that seems to converge also on IP 3 Rs signaling ( Mariotti et al, 2016 , 2018 ; Durkee et al, 2019 ; Caudal et al, 2020 ).…”

Astrocytes, Noradrenaline, α1-Adrenoreceptors, and Neuromodulation: Evidence and Unanswered Questions

“…These numerous mechanisms exemplify the complexity of astrocyte-neuron interactions, and show that astrocytes can modulate circuits in multiple ways depending on the patterns of activity they detect at synapses, as well as the presence of neuromodulators. For interested readers, these last issues are discussed in depth in a parallel publication in this edition of Frontiers in Cellular Neuroscience ( Caudal et al, 2020 ).…”

“…Understanding the biology of α1-NAR signaling in astrocytes (as well as that of other NAR types) will benefit from further advances in the development of genetically encoded biosensors. Changes in astrocyte [Ca 2+ ] i are still considered the best measure of astrocyte activity ( Verkhratsky and Nedergaard, 2018 ; Caudal et al, 2020 ). New genetically encoded calcium indicators (GECIs), such as the jGCaMP7 series, are under intense development, and benefit from improved properties, such as signal-to-noise ratio and steady-state brightness ( Dana et al, 2019 ).…”

Crosstalk among Calcium ATPases: PMCA, SERCA and SPCA in Mental Diseases

“…Furthermore, astrocytes are an integral part of the BBB [ 210 ]. Interestingly, many transport systems responsible for balancing cytosolic Ca 2+ concentration are under feedback control of Ca 2+ /CaM complex [ 211 , 212 , 213 ]. Up to now, the direct regulation of SPCA by CaM has not be detected, but there are several indirect CaM-induced processes that can affect the GA function.…”