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

Jérôme Wahis,Matthew G Holt

doi:10.3389/fncel.2021.645691

Abstract

Noradrenaline is a major neuromodulator in the central nervous system (CNS). It is released from varicosities on neuronal efferents, which originate principally from the main noradrenergic nuclei of the brain – the locus coeruleus – and spread throughout the parenchyma. Noradrenaline is released in response to various stimuli and has complex physiological effects, in large part due to the wide diversity of noradrenergic receptors expressed in the brain, which trigger diverse signaling pathways. In general, however, its main effect on CNS function appears to be to increase arousal state. Although the effects of noradrenaline have been researched extensively, the majority of studies have assumed that noradrenaline exerts its effects by acting directly on neurons. However, neurons are not the only cells in the CNS expressing noradrenaline receptors. Astrocytes are responsive to a range of neuromodulators – including noradrenaline. In fact, noradrenaline evokes robust calcium transients in astrocytes across brain regions, through activation of α1-adrenoreceptors. Crucially, astrocytes ensheath neurons at synapses and are known to modulate synaptic activity. Hence, astrocytes are in a key position to relay, or amplify, the effects of noradrenaline on neurons, most notably by modulating inhibitory transmission. Based on a critical appraisal of the current literature, we use this review to argue that a better understanding of astrocyte-mediated noradrenaline signaling is therefore essential, if we are ever to fully understand CNS function. We discuss the emerging concept of astrocyte heterogeneity and speculate on how this might impact the noradrenergic modulation of neuronal circuits. Finally, we outline possible experimental strategies to clearly delineate the role(s) of astrocytes in noradrenergic signaling, and neuromodulation in general, highlighting the urgent need for more specific and flexible experimental tools.

Highlights

Astrocytes are a major cell type in the central nervous system (CNS), found across brain regions, generally in a non-overlapping fashion (Nimmerjahn and Bergles, 2015)
We focus on noradrenergic neuromodulation through α1-adrenoreceptor (α1-NAR) signaling, as this G Protein Coupled Receptor (GPCR) is highly expressed in astrocytes and is Gq-coupled, leading to intracellular Ca2+ release following noradrenaline receptor (NAR) activation
We aimed to provide an overview of the current state of the art on α1-NAR signaling in astrocytes, and how this relates to NA-mediated neuromodulation

Summary

Introduction

Astrocytes are a major cell type in the central nervous system (CNS), found across brain regions, generally in a non-overlapping fashion (Nimmerjahn and Bergles, 2015). Astrocytes respond to stimuli in an active fashion, often measured as transient changes in intracellular calcium ([Ca2+]i) (Rusakov, 2015; Bazargani and Attwell, 2016; Shigetomi et al, 2016), and can in turn release active signaling molecules (gliosignals) (Vardjan and Zorec, 2015), which induce responses in their target cells (Perea and Araque, 2005; Verkhratsky and Nedergaard, 2018) At the synapse, these small neuroactive molecules have been shown to act on both neuronal and glial cell surface receptors to modulate circuit activity and are more commonly referred to as gliotransmitters (Durkee and Araque, 2019). Astrocytes are coupled into functional networks via gap junctions, allowing crosstalk between otherwise unrelated and relatively distant synapses, a process referred to as lateral regulation of synaptic activity (Covelo and Araque, 2016)

Objectives

Findings

Conclusion