Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable

Xinzhu Yu, Jun Nagai, Maria Marti-Solano, Joselyn S. Soto, Giovanni Coppola, M. Madan Babu, Baljit S. Khakh

Research output: Contribution to journalArticlepeer-review

Abstract

Astrocytes tile the central nervous system and are widely implicated in brain diseases, but the molecular mechanisms by which astrocytes contribute to brain disorders remain incompletely explored. By performing astrocyte gene expression analyses following 14 experimental perturbations of relevance to the striatum, we discovered that striatal astrocytes mount context-specific molecular responses at the level of genes, pathways, and upstream regulators. Through data mining, we also identified astrocyte pathways in Huntington's disease (HD) that were reciprocally altered with respect to the activation of striatal astrocyte G protein-coupled receptor (GPCR) signaling. Furthermore, selective striatal astrocyte stimulation of the Gi-GPCR pathway in vivo corrected several HD-associated astrocytic, synaptic, and behavioral phenotypes, with accompanying improvement of HD-associated astrocyte signaling pathways, including those related to synaptogenesis and neuroimmune functions. Overall, our data show that astrocytes are malleable, using context-specific responses that can be dissected molecularly and used for phenotypic benefit in brain disorders.

Original languageEnglish (US)
Pages (from-to)1146-1162.e10
JournalNeuron
Volume108
Issue number6
DOIs
StatePublished - Dec 23 2020
Externally publishedYes

Keywords

  • GPCR
  • HD
  • RNA sequencing
  • astrocyte
  • behavior
  • calcium
  • context-specific
  • neuroimmune
  • perturbation
  • striatum
  • synaptogenic

ASJC Scopus subject areas

  • Neuroscience(all)

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