Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons

Olli Pietiläinen; Aditi Trehan; Daniel Meyer; Jana Mitchell; Matthew Tegtmeyer; Vera Valakh; Hilena Gebre; Theresa Chen; Emilia Vartiainen; Samouil L Farhi; Kevin Eggan; Steven A McCarroll; Ralda Nehme

doi:10.1016/j.celrep.2022.111988

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons

Cell Rep. 2023 Jan 31;42(1):111988. doi: 10.1016/j.celrep.2022.111988. Epub 2023 Jan 12.

Authors

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA 02138, USA; Neuroscience Center, Helsinki Institute for Life Science, University of Helsinki, 00290 Helsinki, Finland. Electronic address: olli.pietilainen@helsinki.fi.
² Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA 02138, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA 02138, USA; Centre for Gene Therapy and Regenerative Medicine, King's College, London WC2R 2LS, UK.
⁵ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Neuroscience Center, Helsinki Institute for Life Science, University of Helsinki, 00290 Helsinki, Finland.
⁷ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: rnehme@broadinstiute.org.

Abstract

The maturation of neurons and the development of synapses, although emblematic of neurons, also relies on interactions with astrocytes and other glia. Here, to study the role of glia-neuron interactions, we analyze the transcriptomes of human pluripotent stem cell (hPSC)-derived neurons, from 80 human donors, that were cultured with or without contact with glial cells. We find that the presence of astrocytes enhances synaptic gene-expression programs in neurons when in physical contact with astrocytes. These changes in neurons correlate with increased expression, in the cocultured glia, of genes that encode synaptic cell adhesion molecules. Both the neuronal and astrocyte gene-expression programs are enriched for genes associated with schizophrenia risk. Our results suggest that astrocyte-expressed genes with synaptic functions are associated with stronger expression of synaptic genetic programs in neurons, and they suggest a potential role for astrocyte-neuron interactions in schizophrenia.

Keywords: CP: Neuroscience; HiPCS; RNA sequencing; astrocytes; glial cells; human induced pluripotent stem cells; neuron; neuronal development; neuronal differentiation; pluripotent stem cells; schizophrenia; synapse.

Publication types

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

MeSH terms

Astrocytes* / metabolism
Cell Adhesion / genetics
Humans
Neuroglia
Neurons / metabolism
Schizophrenia* / genetics
Schizophrenia* / metabolism
Synapses / physiology

Abstract

Publication types

MeSH terms

Grants and funding