Mapping Astrocyte Transcriptional Signatures in Response to Neuroactive Compounds.

Debosmita Sardar,Chad J Creighton,Junsung Woo,Robert Krencik,Brittney Lozzi,Caroline Cvetkovic,Teng-Wei Huang,Benjamin Deneen

doi:10.3390/ijms22083975

Debosmita Sardar, Chad J Creighton + Show 6 more

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https://doi.org/10.3390/ijms22083975

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Abstract

Astrocytes play central roles in normal brain function and are critical components of synaptic networks that oversee behavioral outputs. Despite their close affiliation with neurons, how neuronal-derived signals influence astrocyte function at the gene expression level remains poorly characterized, largely due to difficulties associated with dissecting neuron- versus astrocyte-specific effects. Here, we use an in vitro system of stem cell-derived astrocytes to identify gene expression profiles in astrocytes that are influenced by neurons and regulate astrocyte development. Furthermore, we show that neurotransmitters and neuromodulators induce distinct transcriptomic and chromatin accessibility changes in astrocytes that are unique to each of these neuroactive compounds. These findings are highlighted by the observation that noradrenaline has a more profound effect on transcriptional profiles of astrocytes compared to glutamate, gamma-aminobutyric acid (GABA), acetylcholine, and serotonin. This is demonstrated through enhanced noradrenaline-induced transcriptomic and chromatin accessibility changes in vitro and through enhanced calcium signaling in vivo. Taken together, our study reveals distinct transcriptomic and chromatin architecture signatures in astrocytes in response to neuronal-derived neuroactive compounds. Since astrocyte function is affected in all neurological disorders, this study provides a new entry point for exploring genetic mechanisms of astrocyte–neuron communication that may be dysregulated in disease.

Highlights

Astrocytes are a non-neuronal cell type that comprise at least 30% of the cellular constituency of our brains [1]
Tremendous advances defining the role of astrocytes in cross talk with neurons have been made, detailed mechanisms with respect to gene expression programs associated with astrocyte–neuron communication have remained elusive
We used an in vitro system to define transcriptomic and chromatin accessibility programs in astrocytes that are stimulated by neurons and neuroactive chemicals

Summary

Introduction

Astrocytes are a non-neuronal cell type that comprise at least 30% of the cellular constituency of our brains [1]. Over the past two decades, astrocytes have been shown to be actively involved in cross talk with neurons [2,3,4]. This interplay is possible since astrocytes express various receptors that are activated by neuronal signals, which subsequently generate calcium waves within astrocytes. Calcium signaling-dependent astrocyte–neuron communication enables astrocytes to be critical mediators of information transfer in our brains [5,6,7]. Significant advances have been made regarding how astrocytes contribute to neuronal information processing [9,10,11,12,13,14,15], the gene expression networks that direct astrocyte–neuron communication still remain largely unknown

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