Astrocytes—The Ultimate Effectors of Long-Range Neuromodulatory Networks?

Abstract

It was long thought that astrocytes, given their lack of electrical signaling, were not involved in communication with neurons. However, we now know that one astrocyte on average maintains and regulates the extracellular neurotransmitter and potassium levels of more than 140,000 synapses, both excitatory and inhibitory, within their individual domains, and form a syncytium that can propagate calcium waves to affect distant cells via release of "gliotransmitters" such as glutamate, ATP, or adenosine. Neuromodulators can affect signal-to-noise and frequency transmission within cortical circuits by effects on inhibition, allowing for the filtering of relevant vs. irrelevant stimuli. Moreover, synchronized "resting" and desynchronized "activated" brain states are gated by short bursts of high-frequency neuromodulatory activity, highlighting the need for neuromodulation that is robust, rapid, and far-reaching. As many neuromodulators are released in a volume manner where degradation/uptake and the confines of the complex CNS limit diffusion distance, we ask the question-are astrocytes responsible for rapidly extending neuromodulator actions to every synapse? Neuromodulators are known to influence transitions between brain states, leading to control over plasticity, responses to salient stimuli, wakefulness, and sleep. These rapid and widespread state transitions demand that neuromodulators can simultaneously influence large and diverse regions in a manner that should be impossible given the limitations of simple diffusion. Intriguingly, astrocytes are ideally situated to amplify/extend neuromodulator effects over large populations of synapses given that each astrocyte can: (1) ensheath a large number of synapses; (2) release gliotransmitters (glutamate/ATP/adenosine) known to affect inhibition; (3) regulate extracellular potassium that can affect excitability and excitation/inhibition balance; and (4) express receptors for all neuromodulators. In this review article, we explore the hypothesis that astrocytes extend and amplify neuromodulatory influences on neuronal networks via alterations in calcium dynamics, the release of gliotransmitters, and potassium homeostasis. Given that neuromodulatory networks are at the core of our sleep-wake cycle and behavioral states, and determine how we interact with our environment, this review article highlights the importance of basic astrocyte function in homeostasis, general cognition, and psychiatric disorders.

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

“…Interestingly, similar effects on CNS circuits have also been attributed to neuromodulators ( Pacholko et al, 2020 ). Indeed, neuromodulators often exert effects on numerous, otherwise unrelated, synapses to change global CNS activity, in response to specific environmental or internal stimuli ( Avery and Krichmar, 2017 ).…”

“…Crucially, in the case of noradrenergic neurons this figure appears to be lower, with up to 95% of NA varicosities being devoid of synaptic contacts in cortex ( Vizi et al, 2010 ). This morphological evidence is a key component of the hypothesis that astrocytes are important targets of noradrenergic signaling ( Stone and Ariano, 1989 ; Hirase et al, 2014 ; Fuxe et al, 2015 ; Pacholko et al, 2020 ).…”

“…A shared trait among neuromodulators is their effects on inhibitory neurotransmission in the CNS, notably in the cortex ( Pacholko et al, 2020 ). By acting on the inhibitory system, neuromodulators change the gain of specific inputs into cortical circuits, affecting the signal-to-noise ratio of relevant information perceived in the environment ( Aston-Jones and Cohen, 2005 ), shifting the global brain state ( Lee and Dan, 2012 ), and ultimately affecting behavior ( Berridge and Waterhouse, 2003 ).…”

“…However, none of these studies could conclusively show which cell type(s) expressed α1A-NAR and were activated by NA. We have already noted that astrocytes are increasingly recognized as the targets of various neuromodulators ( Kjaerby et al, 2017 ; Kastanenka et al, 2020 ; Pacholko et al, 2020 ), including NA ( O’Donnell et al, 2012 ), and direct astrocyte activation seems to mimic the shifts in brain state produced by neuromodulators ( Poskanzer and Yuste, 2016 ). The most plausible explanation is that α1A-NAR are expressed by both astrocytes and interneurons, with the functional effects of NA being linked to the concerted activation of both cell types.…”

“…Indeed, neuromodulators often exert effects on numerous, otherwise unrelated, synapses to change global CNS activity, in response to specific environmental or internal stimuli ( Avery and Krichmar, 2017 ). Over the past several years, there has been accumulating evidence that several neuromodulators may well exert their effects through astrocytes ( Ma et al, 2016 ; Papouin et al, 2017 ; Robin et al, 2018 ; Corkrum et al, 2019 , 2020 ; Mu et al, 2019 ; Wahis et al, 2021b ), a subject which is also reviewed in Pacholko et al (2020) . In this review, 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 Ca 2+ release following noradrenaline receptor (NAR) activation.…”