A concerted neuron–astrocyte program declines in ageing and schizophrenia

Emi Ling (), James Nemesh, Melissa Goldman, Nolan Kamitaki, Nora Reed, Robert E. Handsaker, Giulio Genovese, Jonathan S. Vogelgsang, Sherif Gerges, Seva Kashin, Sulagna Ghosh, John M. Esposito, Kiely Morris, Daniel Meyer, Alyssa Lutservitz, Christopher D. Mullally, Alec Wysoker, Liv Spina, Anna Neumann, Marina Hogan, Kiku Ichihara, Sabina Berretta () and Steven A. McCarroll ()
Additional contact information
Emi Ling: Broad Institute of MIT and Harvard
James Nemesh: Broad Institute of MIT and Harvard
Melissa Goldman: Broad Institute of MIT and Harvard
Nolan Kamitaki: Broad Institute of MIT and Harvard
Nora Reed: Broad Institute of MIT and Harvard
Robert E. Handsaker: Broad Institute of MIT and Harvard
Giulio Genovese: Broad Institute of MIT and Harvard
Jonathan S. Vogelgsang: McLean Hospital
Sherif Gerges: Broad Institute of MIT and Harvard
Seva Kashin: Broad Institute of MIT and Harvard
Sulagna Ghosh: Broad Institute of MIT and Harvard
John M. Esposito: McLean Hospital
Kiely Morris: McLean Hospital
Daniel Meyer: Broad Institute of MIT and Harvard
Alyssa Lutservitz: Broad Institute of MIT and Harvard
Christopher D. Mullally: Broad Institute of MIT and Harvard
Alec Wysoker: Broad Institute of MIT and Harvard
Liv Spina: Broad Institute of MIT and Harvard
Anna Neumann: Broad Institute of MIT and Harvard
Marina Hogan: Broad Institute of MIT and Harvard
Kiku Ichihara: Broad Institute of MIT and Harvard
Sabina Berretta: Broad Institute of MIT and Harvard
Steven A. McCarroll: Broad Institute of MIT and Harvard

Nature, 2024, vol. 627, issue 8004, 604-611

Abstract: Abstract Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people’s cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22–97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing—two conditions that involve declines in cognitive flexibility and plasticity1,2—cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

Date: 2024
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DOI: 10.1038/s41586-024-07109-5

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