Publication Date
5-1-2023
Journal
Nature
DOI
10.1038/s41586-023-06010-x
PMID
37100909
PMCID
PMC10733939
PubMedCentral® Posted Date
12-21-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Astrocytes, gamma-Aminobutyric Acid, Neurons, Synapses, Cell Shape, Receptors, GABA-B, SOX9 Transcription Factor, NFI Transcription Factors, Gene Expression Regulation, Neural Inhibition
Abstract
Communication between neurons and glia plays an important role in establishing and maintaining higher order brain function1. Astrocytes are endowed with complex morphologies which places their peripheral processes in close proximity to neuronal synapses and directly contributes to their regulation of brain circuits2–4. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation5–7; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unknown. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABABR and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABABR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together our studies identify input from inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.