Sculpting Astrocyte Diversity through Circuits and Transcription

Abstract

Astrocytes are the most abundant glial cell in the central nervous system and occupy a wide range of roles that are essential for brain function. Over the past few years, evidence has emerged that astrocytes exhibit cellular and molecular heterogeneity, raising the possibility that subsets of astrocytes are functionally distinct and that transcriptional mechanisms are involved in encoding this prospective diversity. In this review, we focus on three emerging areas of astrocyte biology: region-specific circuit regulation, molecular diversity, and transcriptional regulation. This review highlights our nascent understanding of how molecular diversity is converted to functional diversity of astrocytes through the lens of brain region–specific circuits. We articulate our understanding of how transcriptional mechanisms regulate this diversity and key areas that need further exploration to achieve the overarching goal of a functional taxonomy of astrocytes in the brain.

Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

“…Neuronal activity-dependent astrocyte transcriptional and epigenomic changes control olfactory processing. Neuronal activity induces widespread transcriptional changes in astrocytes (1), which is exemplified by Sox9 DNA-binding changes after odor-evoked neuronal activation (2). Slc22a3 (3) represents a Sox9-regulated and activitydependent olfactory bulb target that controls astrocytic serotonin (5HT) levels to coordinate histone serotonylation (4), a previously uncharacterized epigenomic mediator of astrocytic GABA release that ultimately affects olfactory processing (5).…”

“…◥ NEUROSCIENCE Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation Debosmita Sardar 1,2 , Yi-Ting Cheng 1,2,3 †, Junsung Woo 1,2 †, Dong-Joo Choi 1,2 , Zhung-Fu Lee 1,2,4 , Wookbong Kwon 1,2 , Hsiao-Chi Chen 1,2,5 , Brittney Lozzi 1,2,6 , Alexis Cervantes 1,2 , Kavitha Rajendran 1,2 , Teng-Wei Huang 1 , Antrix Jain 7 , Benjamin R. Arenkiel 3,8,9 , Ian Maze 10,11,12 , Benjamin Deneen 1,2,3,4,13 * Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of Slc22a3 as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb.…”

“…A strocytes are intimately associated with neuronal activity and neurotransmission and participate in a host of essential roles that facilitate synaptic function (1)(2)(3)(4)(5). Cellintrinsic activation of G protein subunit G q or G i signaling and associated calcium activity in astrocytes can influence a multitude of behavioral outputs (6)(7)(8)(9)(10).…”

Astrocytes as master modulators of neural networks: Synaptic functions and disease‐associated dysfunction of astrocytes

“…neurotransmitters and signaling peptides. 9 This review aims to summarize recent findings regarding the roles of protoplasmic and fibrous astrocytes at the synapse and in the white matter, respectively, with particular attention to their roles in neurodevelopmental and neuropsychiatric disorders.…”

Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

“…Astrocytes are intimately associated with neuronal activity and neurotransmission, participating in a host of essential roles that facilitate synaptic function (1)(2)(3)(4)(5). A series of prior studies have shown that cell intrinsic activation of Gq-or Gi-signaling and associated Ca 2+ activity in astrocytes can influence a multitude of behavioral outputs, providing key evidence for astrocytic modulation of circuit function (6)(7)(8)(9)(10).…”