The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain

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SUMMARY

Aging brains undergo cognitive decline, associated with decreased neuronal synapse number and function and altered metabolism. Astrocytes regulate neuronal synapse formation and function in development and adulthood, but whether these properties change during aging, contributing to neuronal dysfunction, is unknown. We addressed this by generating aged and adult astrocyte transcriptomes from multiple mouse brain regions. These data provide a comprehensive RNA-seq database of adult and aged astrocyte gene expression, available online as a resource. We identify astrocyte genes altered by aging across brain regions and regionally unique aging changes. Aging astrocytes show minimal alteration of homeostatic and neurotransmission-regulating genes. However, aging astrocytes upregulate genes that eliminate synapses and partially resemble reactive astrocytes. We further identified heterogeneous expression of synapse-regulating genes between astrocytes from different cortical regions. We find that alterations to astrocytes in aging create an environment permissive to synapse elimination and neuronal damage, potentially contributing to aging-associated cognitive decline.

In Brief

The aging brain has reduced synapse number and decreased neuronal activity, functions regulated by neighboring astrocytes. Boisvert et al. investigated if aging astrocytes are contributing to these changes and found that aged astrocytes show increased expression of genes for inflammatory and synapse elimination pathways and decreased cholesterol synthesis enzymes.

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Most cited references 28

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Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.

Karen Christopherson, Erik Ullian, Caleb Stokes … (2005)

The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.

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Diversity of astrocyte functions and phenotypes in neural circuits.

Baljit Khakh, Michael Sofroniew (2015)

Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease.

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Cell-type-specific isolation of ribosome-associated mRNA from complex tissues.

Elisenda Sanz, Linghai Yang, Thomas Su … (2009)

Gene profiling techniques allow the assay of transcripts from organs, tissues, and cells with an unprecedented level of coverage. However, most of these approaches are still limited by the fact that organs and tissues are composed of multiple cell types that are each unique in their patterns of gene expression. To identify the transcriptome from a single cell type in a complex tissue, investigators have relied upon physical methods to separate cell types or in situ hybridization and immunohistochemistry. Here, we describe a strategy to rapidly and efficiently isolate ribosome-associated mRNA transcripts from any cell type in vivo. We have created a mouse line, called RiboTag, which carries an Rpl22 allele with a floxed wild-type C-terminal exon followed by an identical C-terminal exon that has three copies of the hemagglutinin (HA) epitope inserted before the stop codon. When the RiboTag mouse is crossed to a cell-type-specific Cre recombinase-expressing mouse, Cre recombinase activates the expression of epitope-tagged ribosomal protein RPL22(HA), which is incorporated into actively translating polyribosomes. Immunoprecipitation of polysomes with a monoclonal antibody against HA yields ribosome-associated mRNA transcripts from specific cell types. We demonstrate the application of this technique in brain using neuron-specific Cre recombinase-expressing mice and in testis using a Sertoli cell Cre recombinase-expressing mouse.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 13 January 2018

Publication date (Print): 02 January 2018

Publication date PMC-release: 24 January 2018

Volume: 22

Issue: 1

Pages: 269-285

Affiliations

[1 ]Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA

[2 ]Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA

[3 ]Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA

Author notes

[* ]Correspondence: nallen@ 123456salk.edu

[4]

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Article

Manuscript ID: NIHMS934753

DOI: 10.1016/j.celrep.2017.12.039

PMC ID: 5783200

PubMed ID: 29298427

SO-VID: 2dcb1076-9e68-4b85-85f1-cf5a545251c7

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain

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In Brief

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Most cited references 28

Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.

Diversity of astrocyte functions and phenotypes in neural circuits.

Cell-type-specific isolation of ribosome-associated mRNA from complex tissues.

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