Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable

Neuron. 2020 Dec 23;108(6):1146-1162.e10. doi: 10.1016/j.neuron.2020.09.021. Epub 2020 Oct 20.


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.

Keywords: GPCR; HD; RNA sequencing; astrocyte; behavior; calcium; context-specific; neuroimmune; perturbation; striatum; synaptogenic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Corpus Striatum / metabolism*
  • Data Mining
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Mice
  • Neurons / metabolism
  • Signal Transduction / physiology
  • Synapses / metabolism