Activity-dependent modulation of synapse-regulating genes in astrocytes
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Evaluation Summary:
This paper describes the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. Using bulk RNAseq and detailed histology, they demonstrate that expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (using vGlut2 KO mice) and astrocyte calcium activity in vivo (using IP3R2 KO mice). They further demonstrate astrocyte molecular changes using snRNA-seq in VGlut2 cKO and Ip3r2 cKO mice. Collectively, these results show that neuronal activity drives the changes in astrocyte function and layer-specific expression of synaptogenic secreted proteins. Overall, this a rigorous and well conducted study that provides important and new information on astrocyte diversity, neuron-astrocyte interactions during development, and mechanisms underlying the expression of key astrocyte synaptogenic genes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Astrocytes regulate the formation and function of neuronal synapses via multiple signals; however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development is also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single-nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.
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Evaluation Summary:
This paper describes the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. Using bulk RNAseq and detailed histology, they demonstrate that expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (using vGlut2 KO mice) and astrocyte …
Evaluation Summary:
This paper describes the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. Using bulk RNAseq and detailed histology, they demonstrate that expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (using vGlut2 KO mice) and astrocyte calcium activity in vivo (using IP3R2 KO mice). They further demonstrate astrocyte molecular changes using snRNA-seq in VGlut2 cKO and Ip3r2 cKO mice. Collectively, these results show that neuronal activity drives the changes in astrocyte function and layer-specific expression of synaptogenic secreted proteins. Overall, this a rigorous and well conducted study that provides important and new information on astrocyte diversity, neuron-astrocyte interactions during development, and mechanisms underlying the expression of key astrocyte synaptogenic genes.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This paper describes, in extensive detail, the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. Using bulk RNAseq and detailed histology, they determine the changing astrocyte transcriptome during VC development and show the expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits.
In the second part of the paper, the authors set out to understand what drives this layer specific expression of key synaptogenic genes by attenuating glutamatergic transmission and blocking astrocyte calcium signaling. These results demonstrate that neuronal activity drives the changes in astrocyte …
Reviewer #1 (Public Review):
This paper describes, in extensive detail, the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. Using bulk RNAseq and detailed histology, they determine the changing astrocyte transcriptome during VC development and show the expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits.
In the second part of the paper, the authors set out to understand what drives this layer specific expression of key synaptogenic genes by attenuating glutamatergic transmission and blocking astrocyte calcium signaling. These results demonstrate that neuronal activity drives the changes in astrocyte function and layer-specific expression of synaptogenic secreted proteins. Collectively, the authors convincingly demonstrate that neuronal cell-type and astrocyte interactions drive VC development. These findings have broader implications for development of the brain and neural circuits in health and disease.
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Reviewer #2 (Public Review):
In this paper by Allen and colleagues the development of cortical astrocytes is examined using molecular profiling approaches. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. These are important and timely questions that need to be addressed and also touch on astrocyte diversity, an emerging topic in glial biology. Furthermore, this paper rigorously analyzes the expression characteristics of key synaptogenic genes (GPC- and Thbs- family) that are expressed in developing astrocytes. Figures 1-3 assess developing astrocytes in the cortex and very elegantly show that these synaptogenic genes are expressed in a spatial and temporal specific …
Reviewer #2 (Public Review):
In this paper by Allen and colleagues the development of cortical astrocytes is examined using molecular profiling approaches. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. These are important and timely questions that need to be addressed and also touch on astrocyte diversity, an emerging topic in glial biology. Furthermore, this paper rigorously analyzes the expression characteristics of key synaptogenic genes (GPC- and Thbs- family) that are expressed in developing astrocytes. Figures 1-3 assess developing astrocytes in the cortex and very elegantly show that these synaptogenic genes are expressed in a spatial and temporal specific manner across different layers-this is the very first rigorous analysis of the expression profiles of these genes across space and time. Figures 4/5 are neuronal and astrocyte manipulations, showing that broad expression of these genes is regulated by neuronal activity and ca2+ activity in astrocytes; again a very nice demonstration of how astrocyte gene expression profiles are influenced by the neuronal microenvironment. Finally, figures 6/7 are single cell RNA-Seq analysis of developing astrocytes and importantly reinforces the concept that changes in neuronal activity alters astrocyte profiles and subpopulations. Together, this a very well conducted study that provides important and new information on the following topics: astrocyte diversity, neuron-astrocyte interactions during development, and the ground truth underlying the expression of key astrocyte synaptogenic genes. I don't have any real concerns about the data or interpretation. This is an excellent paper that will provide a new framework for understanding how neurons shape developing astrocytes in the cortex.
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Reviewer #3 (Public Review):
The authors investigated astrocytic expression of known synapse-regulating genes and how they changed during different developmental stages at temporal and spatial levels using experimental strategies of astrocyte RNA-seq and FISH. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (vGlut2 KO mice) and astrocyte calcium activity in vivo (IP3R2 KO mice). Finally, the authors investigated astrocyte molecular changes in an unbiased way using snRNA-seq for VGlut2 cKO and Ip3r2 cKO mice.
Overall, the findings regarding astrocytic gene expression alterations of synapse-regulating genes in the visual cortex regulated by neuronal input from the thalamus and astrocyte calcium activity are novel and of interest to the field. The …
Reviewer #3 (Public Review):
The authors investigated astrocytic expression of known synapse-regulating genes and how they changed during different developmental stages at temporal and spatial levels using experimental strategies of astrocyte RNA-seq and FISH. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (vGlut2 KO mice) and astrocyte calcium activity in vivo (IP3R2 KO mice). Finally, the authors investigated astrocyte molecular changes in an unbiased way using snRNA-seq for VGlut2 cKO and Ip3r2 cKO mice.
Overall, the findings regarding astrocytic gene expression alterations of synapse-regulating genes in the visual cortex regulated by neuronal input from the thalamus and astrocyte calcium activity are novel and of interest to the field. The experiments are well designed and well performed by experts in the area with a track record of high quality work.
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