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

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.

Noradrenergic Signaling in Astrocytes Influences Mammalian Sleep Homeostasis

“…There are, however, several differences in signaling between astroglial α- and β-ARs that suggest that β-ARs may be the critical subtype in this process. Astroglial α1- and α2-ARs have greater affinity for NA [ 38 ] and trigger rapid changes in intracellular astroglial Ca 2+ via activation of G q and G i pathways, respectively [ 39 ]. This makes them well-suited for detecting fast changes in NA release associated with specific behavioral contexts (e.g., during learning, attention) or modulating rapid changes in synaptic transmission.…”

“…This makes them well-suited for detecting fast changes in NA release associated with specific behavioral contexts (e.g., during learning, attention) or modulating rapid changes in synaptic transmission. In contrast, the β2-AR has lower affinity for NA [ 38 ] and is coupled to G s signaling which upregulates cyclic adenosine monophosphate (cAMP) [ 39 ], and secondarily Ca 2+ [ 16 ], under slower time scales [ 38 ]. For example, astroglial cAMP takes longer to peak and decline compared to Ca 2+ in response to optogenetic stimulation of NA cortical terminals or fear-conditioned foot shock in vivo [ 38 ].…”

Photonics tools begin to clarify astrocyte calcium transients

“… 1 , 46 Other than glutamate, numerous G protein coupled receptors such as protein receptors, protein CB1 receptors, or protein alpha adrenergic receptors can also cause increases in calcium via convergence on an signaling pathway. 47 – 51 …”

“…1,46 Other than glutamate, numerous G protein coupled receptors such as G i protein GABA B receptors, G i protein CB1 receptors, or G q protein alpha adrenergic receptors can also cause increases in calcium via convergence on an IP 3 R signaling pathway. [47][48][49][50][51] Although calcium transients rely in part on release from intracellular stores, influx of calcium through transmembrane channels or transporters is not to be overlooked. 52 Neurotransmitter transporters such as GLT-1 or GAT-3 can generate increases in intracellular sodium during cotransport, which ultimately reverses the activity of the Na þ ∕Ca 2þ exchanger (NCX), resulting in calcium influx.…”

The Multifaceted Neurotoxicity of Astrocytes in Ageing and Age-Related Neurodegenerative Diseases: A Translational Perspective

“…Indeed, astrocytes express numerous noradrenergic receptors at their surface (α and β), and NA modulates their metabolic activity, glutamate uptake, glycogen production, and glucose metabolism ( O’Donnell et al, 2012 ), but also their calcium activity ( Ding et al, 2013 ; Oe et al, 2020 ). NA has been also directly involved in astrocyte mediated memory consolidation ( Gao et al, 2016 ; Wahis and Holt, 2021 ). NA can downregulate transcription of pro-inflammatory genes (such as TNF-α, IL-1β, and iNOS), and upregulate anti-inflammatory molecules (such as HSP-70 and MCP-1) in astrocytes and microglia ( Heneka et al, 2010 ; Chalermpalanupap et al, 2013 ).…”